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Characterization of single nucleotide polymorphisms of cytochrome P450 in an Australian deceased sample
Jennifer L. Pilgrim, Yarimar Ruiz, Alejandro Gesteira, Raquel Cruz, Dimitri Gerostamoulos, Angel Carracedo and Olaf  H. Drummer
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22299824 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00220]


Absorption, Disposition, and Pharmacokinetics of Saponins from Chinese Medicinal Herbs: What Do We Know and What Do We Need to Know More?
Ke Yu, Feng Chen and Chuan Li
[Abstract] [Purchase Article] [PMID: 22292787 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00222]


Metabolite profiling and characterization for medicinal herbal remedies
Min Yang, Chunru Cheng, Junling Yang and De-an Guo
[Purchase Article] [PMID: 22292788 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00223]


Herb-Drug Interactions and Mechanistic and Clinical Considerations
Shu-Ming He, Kevin B. Sneed, Xiao-Wu Chen, Chuanhai Cao and Shu-Feng Zhou
[Abstract] [Purchase Article] [PMID: 22292789 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00224]


Intestinal Absorption and Presystemic Elimination of Various Chemical Constituents Present in GBE50 Extract, a Standardized Extract of Ginkgo Biloba Leaves
Li Li, Yuansheng Zhao, Feifei Du, Junling Yang, Fang Xu, Wei Niu, Yaohui Ren and Chuan Li
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22292790 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00225]


Metabolite profiling and Pharmacokinetics of Herbal Compounds Following Oral Administration of a Cardiovascular Multi-herb Medicine (Qishen Yiqi Pills) in rat
Yufeng Zhang, Peiying Shi, Hong Yao, Qing Shao and Xiaohui Fan
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22292791 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00226]


Aptamers as remarkable diagnostic and therapeutic agents in cancer treatment
Henri-Pierre Lassalle, Sophie Marchal, François Guillemin, Aurélie Reinhard and Lina Bezdetnaya
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22380008 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00234]


In vivo biodistribution, pharmacokinetics, and toxicology of carbon nanotubes
Kai Yang and Zhuang Liu
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22380009 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00235]


Nano-based drug delivery system enhances the oral absorption of lipophilic drugs with extensive presystemic metabolism
Zhiwen Zhang, Fang Gao, Shijun Jiang, Li Ma and Yaping Li
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22380010 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00236]


Dendrimers in cancer therapeutics and diagnosis
Rui Guo and Xiangyang Shi
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22380011 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00237]


Fluorescent Carbon Dots and Nanodiamonds for Biological Imaging: Preparation, Application, Pharmacokinetics and Toxicity
Jia-Hui Liu, Sheng-Tao Yang, Xinxin Chen and Haifang Wang
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22380012 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00238]


Co-delivery strategies based on multifunctional nanocarriers for cancer therapy
Hao Chen, Ying Zhao, Hai Wang, Guangjun Nie and Kaihui Nan
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22380013 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00239]


Toxicological Profile of Therapeutic Nanodelivery Systems
Luis M. Bimbo, Leena Peltonen, Jouni Hirvonen and Hélder A. Santos
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22380014 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00240]


Impacts of nanoparticles on cardiovascular diseases: modulating metabolism and function of endothelial cells
Jie Meng, Xian-da Yang, Lee Jia, Xing-Jie Liang and Chen Wang
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22380015 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00241]


Nanoparticles improve biological functions of phthalocyanine photosensitizers used for photodynamic therapy
Xiao Jia and Lee Jia
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22380016 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00242]


Fullerenes for Cancer Diagnosis and Therapy: Preparation, Biological and Clinical Perspectives
Zhiyun Chen, Ruoqing Mao and Ying Liu
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22380017 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00243]


Sex Differences In The Clearance Of Cyp3a4 Substrates: Exploring Possible Reasons For The Substrate Dependency And Lack Of Consensus
Manoranjenni Chetty, Donald Mattison and Amin Rostami-Hodjegan
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22452452 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00244]


Physiologically-based Pharmacokinetic (PBPK) Models for Assessing the Kinetics of Xenobiotics during Pregnancy: Achievements and Shortcomings
G. Lu, K. Abduljalil, M. Jamei, T.N. Johnson, H. Soltani and A. Rostami-Hodjegan
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22452453 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00245]


Pharmacotherapy in neonatal and pediatric extracorporeal membrane oxygenation (ECMO)
E.D. Wildschut, M.J Ahsman, R.J. Houmes, P. Pokorna, S.N. de Wildt, R.A.A. Mathot and D. Tibboel 
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22452454 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00246]


Ontogeny of Hepatic Glucuronidation; Methods and Results
Elke Henriëtte Josephina Krekels, Meindert Danhof and Dick Tibboel
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22452455 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00247]


Growing up with midazolam in the neonatal and pediatric intensive care
Eleonora L. Swart, Pauline R. Slort and Frans B. Plötz
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22452456 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00248]


Pharmacokinetic Considerations of Perinatal Antiretroviral Therapy
Natella Y. Rakhmanina, Sahera Dirajlal-Fargo, Edmund V. Capparelli and Mark Mirochnik
[Abstract] [Purchase Article] [PMID: 22452457 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00249]


Pharmacogenetics of opioids for the treatment of acute maternal pain during pregnancy and lactation
Parvaz Madadi, Denise Avard and Gideon Koren
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22452458 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00250]


Editorial: Drug Metabolism in Pediatrics, Pregnancy and Lactation
Saskia N. de Wildt
[PMID: 22452459 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00251]


The role of ABC and SLC transporters in the pharmacokinetics of dietary and herbal phytochemicals and their interactions with xenobiotics
Yan Li, Jun Lu and James W. Paxton
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22475331 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00252]


Roles of UDP-glucuronosyltransferases in Phytochemical Metabolism of Herbal Medicines and the Associated Herb-drug Interactions
Li Li, Haihong Hu, Siyun Xu, Quan Zhou and Su Zeng
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22475332 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00253]


Interactions between Phytochemicals from Traditional Chinese Medicines and Human Cytochrome P450 Enzymes
Jing-Jing Wu, Chun-Zhi Ai, Yong Liu, Yan-Yan Zhang, Miao Jiang and Ai-Ping Lv  Ling Yang
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22475333 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00254]


Drug metabolism and pharmacokinetics of nanodrugs from Chinese medicines and natural products
Chang-Xiao Liu, Duan-Yun Si, Xue-Feng Xiao, Xin He and Ya-Zhuo Li
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22475334 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00255]


Pharmacokinetics-Pharmacology Disconnection of Herbal Medicines and Its Potential Solutions with Cellular Pharmacokinetic-Pharmacodynamic Strategy
Jingwei Zhang, Fang Zhou, Meng Lu, Wei Ji, Fang Niu, Weibin Zha,  Xiaolan Wu, Haiping Hao and Guangji Wang
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22475335 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00256]


De-Risking Bio-therapeutics for Possible Drug Interactions Using Cryopreserved Human Hepatocytes
Shannon Dallas, Carlo Sensenhauser, Ameesha Batheja, Monica Singer, Maria Markowska, Cindy Zakszewski, Rao N.V.S. Mamidi, Michael McMillian, Chao Han, Honghui Zhou and Jose Silva
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22475265 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00257]


Drug Interaction Potential of Trastuzumab Emtansine Combined With Pertuzumab in Patients With HER2-Positive Metastatic Breast Cancer
Dan Lu, Howard A Burris III, Bei Wang, E Claire Dees, Javier Cortes, Amita Joshi, Manish Gupta, Joo-Hee Yi, Yu-Waye Chu, Ted Shih, Liang Fang and Sandhya Girish
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22475266 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00258]


Effects of Interleukin 1β (IL-1β) and IL-1β /Interleukin 6 (IL-6) Combinations on
Drug Metabolizing Enzymes in Human Hepatocyte Culture
Leslie J. Dickmann, Sonal K. Patel, Larry C. Wienkers and J. Greg Slatter
[Abstract] [Purchase Article] [PMID: 22475267 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00259]


Animal Models for Evaluation of Drug-Drug Interaction Potential of Biotherapeutics
Eugenia Kraynov, Martin E. Dowty, Odette A. Fahmi and Owen Fields
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22475268 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00260]


Catabolic Fate and Pharmacokinetic Characterization of Trastuzumab Emtansine T-D<1: An Emphasis on Preclinical and Clinical Catabolism
Ben-Quan Shen, Daniela Bumbaca, Ola Saad, Qin Yue, Cinthia V. Pastuskovas, S. Cyrus Khojasteh, Jay Tibbitts, Surinder Kaur, Bei Wang, Yu-Waye Chu, Patricia M LoRusso and Sandhya Girish
[Abstract] [Purchase Article] [BSP/CDM/E-Pub/00261]


Effects of Culture Duration on Gene Expression of P450 Isoforms, Uptake and Efflux Transporters in Primary Hepatocytes Cultured in the Absence and Presence of Interleukin- 6: Implications for Experimental Design for the Evaluation of Downregulatory Effects of Biotherapeutics
Qian Yang, Utkarsh Doshi, Nicole Li and Albert P. Li
[Abstract] [Purchase Article] [PMID: 22475270 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00262]


Disposition and Interaction of Biotherapeutics in Pediatric Populations
Souzan Yanni
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22475271 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00263]


Editorial: Metabolism and drug-drug interaction potential of biotherapeutics
Albert P. Li
[PMID: 22475272 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00264]


Editorial: Absorption, Pharmacokinetics and Disposition of Biodegradable Nanoscale Preparations
YunFeng Lin and ZhiYong Qian
[PMID: 22475211 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00265]


Function and regulation of the Cyp2a5/CYP2A6 genes in response to toxic insults in the liver
A’edah Abu-Bakar, Jukka Hakkola, Risto Juvonen, Minna Rahnasto-Rilla, Hannu Raunio and Matti A Lang
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00266]


Evaluation of the Physicochemical and Biopharmaceutical properties of Fluoro-Indomethacin
Michela M. Mori, Anu J. Airaksinen, Jouni T. Hirvonen, Hélder A. Santos and Carla M. Caramella
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00267]


Improving Oral Absorption via Drug-Loaded Nanocarriers: Absorption Mechanisms, Intestinal Models and Rational Fabrication
Mohammad-Ali Shahbazi and Hélder A. Santos
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00268]


Precision-cut intestinal slices as in vitro tool for studies on drug metabolism
Geny M.M. Groothuis and Inge A.M. de Graaf
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00269]


In vitro methods to study the interplay of drug metabolism and efflux in the intestine
Sanna Siissalo and Aki T. Heikkinen
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00270]


Do the Recommended Standards for In Vitro Biopharmaceutic Classification of Drug Permeability Meet the "Passive Transport" Criterion for Biowaivers?
Žakelj Simon, Berginc Katja, Roškar Robert, Kraljič Bor and Kristl Albin
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00271]


Aspirin as a chemoprevention agent for Colorectal cancer
Chun Seng Lee, Deirdre McNamara and Colm Antoine O’Morain
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00272]


Is the autophagy induced by thiopurines beneficial or deleterious?
Luis G. Guijarro, Irene D. Román, M. Dolores Fernández-Moreno,  Javier P. Gisbert and Borja Hernández-Breijo
[Abstract] [Purchase Article] [BSP/CDM/E-Pub/00273]


The influence of CYP2C19 genetic polymorphism on the pharmacokinetics/pharmacodynamics of proton pump inhibitor-containing Helicobacter pylori treatments
D.R. Serrano, S. Torrado, S. Torrado-Santiago and J.P. Gisbert
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00274]


Drug Treatment of Eosinophilic Oesophagitis
S. O'Donnell, OB. Kelly and C. O'Morain
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00275]


Utility of assessing thiopurine S-methyltransferase polymorphisms before azathioprine therapy
Teresa Cabaleiro, Manuel Román, Javier P. Gisbert and Francisco Abad-Santos
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00276]


Vitamin D: New Roles and Therapeutic Potential in Inflammatory Bowel Disease
Tara Raftery, Colm O’Morain and Maria O’Sullivan
[Abstract] [Purchase Article] [BSP/CDM/E-Pub/00277]


Strategies For Improving The Quantitative Bioanalytical Performance Of Lc–Ms In Pharmacokinetic Studies
Li Li, Dandan Tian, Junling Yang, Feng Chen, Ke Yu and Yan Sun
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00278]


Isotopic labeling of metabolites in drug discovery applications
Jacobo Iglesias, Lekha Sleno and Dietrich A. Volmer
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00279]


Liquid Chromatography-Mass Spectrometric Multiple Reaction Monitoring-based Strategies for Expanding Targeted Profiling towards Quantitative Metabolomics
Bin Guo, Bo Chen, Aiming Liu, Weitao Zhu and Shouzhuo Yao
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00280]


LC/MS Based Tools and Strategies on Qualitative and Quantitative Analysis of Herbal Components in Complex Matrixes
Liang Wu, Haiping Hao and Guangji Wang
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00281]


Lc-Ms Based Screening And Targeted Profiling Methods For Complex Plant: Coffee A Case Study
Jeane Santos da Rosa, Otniel Freitas-Silva, Sidney Pacheco, Ronoel Luiz de Oliveira Godoy and Claudia Maria Moraes Rezende
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00282]


Importance of Metabolic Activation Study to the Safe Use of Chinese Herbal Medicines
Bin Ma, Na Li and Ge Lin
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00283]


Metabolic Conversion from Co-existing Ingredient Leading to Significant Systemic
Exposure of Z-butylidenephthalide, a Minor Ingredient in Chuanxiong Rhizoma in
Rat
Ru Yan, Nga Ling Ko, Bin Ma, Yun Kau Tam and Ge Lin
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00284]


Measurement of CYP1A2 Activity: A Focus on Caffeine as a Probe
Vidya Perera, Annette S. Gross and Andrew J. McLachlan
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00285]


Uptake and metabolism of the short-chain fatty acid butyrate, a critical review of the literature
Stuart M. Astbury and Bernard M. Corfe
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00286]


Active Metabolites Resulting from Decarboxylation, Reduction and Ester Hydrolysis of Parent Drugs
I. Hartyánszky, H, Kalász , E. Adeghate , Zs. Gulyás, M.Y. Hasan, K. Tekes, A. Adem and P. Sótonyi
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00287]


Summary of Information on the Effects of Ionizing and Non-ionizing Radiation on Cytochrome P450 and Other Drug Metabolizing Enzymes and Transporters
Slobodan Rendic and F. Peter Guengerich
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00288]


Physiologically Based Pharmacokinetic Models: Integration of In Silico Approaches with Micro Cell Culture Analogues
T. Maguire, A. Chen and M.L.Yarmush
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00289]


Intracellular Disposition of Methotrexate in Acute Lymphoblastic Leukemia in Children
Tiphaine Adam de Beaumais and Evelyne Jacqz-Aigrain
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00290]


Comparison of Cytochrome P450 2C Subfamily Members in Terms of Drug Oxidation Rates and Substrate Inhibition
Toshiro Niwa and Hiroshi Yamazaki
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00291]


Implications of Nanoscale Based Drug Delivery Systems in Delivery and Targeting Tubulin Binding Agent, Noscapine in Cancer Cells
Ramesh Chandra, Jitender Madan, Prashant Singh, Ankush Chandra, Pradeep Kumar, Vritika Tomar and Sujata K. Dass
[Abstract] [FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00292]

Abstracts


Characterization of single nucleotide polymorphisms of cytochrome P450 in an Australian deceased sample
Jennifer L. Pilgrim, Yarimar Ruiz, Alejandro Gesteira, Raquel Cruz, Dimitri Gerostamoulos, Angel Carracedo and Olaf  H. Drummer
[FULL-TEXT INQUIRY] [PMID: 22299824 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00220]

The genetically variable CYP450 isozymes are responsible for the metabolism of up to 80% of commonly used drugs, many of which are detected in cases of unexpected or suspicious death in Australia. The aim of this study was to examine the genetic profiles of individuals in a cohort of Australian deceased individuals dying of drug toxicity (219), natural disease (150), external injury (109) or unascertained (8) causes, to determine if there was an over-representation of individuals with a genetic predisposition to altered drug metabolism in cases attributed to drug toxicity compared with other causes. Single nucleotide polymorphisms (SNP) of CYP1A2, 2C9, 2C19, 2D6, 3A4 and 3A5 were analyzed. There were 27 cases (6.1%) that were CYP2D6 poor metabolizers (PM) and an additional 8 cases (1.7 %) that were CYP2C19 PMs. Around 31% of the cases were CYP2D6 intermediate-poor metabolizers, with a number of cases exhibiting drug combinations that were likely to have caused pharmacokinetic or pharmacodynamic interactions. There was no correlation between cause of death type and CYP2D6 metabolizer status. Increased enzyme activity was also indicated by the presence of hyperinducible variants such as CYP1A2*1F, which was observed at a frequency of 48%.
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Absorption, Disposition, and Pharmacokinetics of Saponins from Chinese Medicinal Herbs: What Do We Know and What Do We Need to Know More?
Ke Yu, Feng Chen and Chuan Li
[Purchase Article] [PMID: 22292787 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00222]

Saponins are a group of amphiphilic glycosides containing one or more sugar chains linked to a nonpolar triterpene or steroid aglycone skeleton, which are believed to be responsible for the pharmacological activities of many Chinese medicinal herbs. The purpose of this paper is to summarize the contemporary knowledge of the absorption, disposition, and pharmacokinetics of some important saponins, including ginsenosides, licorice saponins, dioscorea saponins, astragalosides, and saikosaponins. Poor intestinal absorption of saponins is mainly due to their unfavorable physicochemical traits, such as large molecular mass (>500 Da), high hydrogen-bonding capacity (>12), and high molecular flexibility (>10), that underlie poor membrane permeability. Rapid and extensive biliary excretion is another primary factor that limits the oral bioavailability of most saponins. However, several saponins, including ginsenosides Ra3, Rb1, Rc, and Rd, and dioscin, are excreted slowly into the bile and in turn have significantly long elimination half lives (7–25 h in rats). These long-circulating saponins may be used as pharmacokinetic markers to substantiate systemic exposure to the ingested herb extracts. In addition to biliary excretion for elimination of most saponins unchanged, renal excretion may also be important for certain saponins. Saponins can be hydrolyzed by the colonic microflora. After absorption, the deglycosylated aglycones undergo phase I and/or II metabolism by the host. In line with the poor permeability, saponin concentrations in most rat tissues are lower than the concurrent plasma level and the brain level is usually very low. However, the liver concentrations of many saponins, as well as the kidney levels of certain saponins, can be quite high, which involves transporter-mediated uptake mechanisms. Repeated p.o. ingestion of glycyrrhizin appears to be able to induce CYP3A in rodents and humans, while several deglycosylated products of ginsenosides can moderately inhibit CYP activities in vitro with IC50 values of 10–50 μM. More research is required for elucidation of the absorption, disposition, and pharmacokinetics of multiple saponins to enhance understanding which saponins are most likely to exert pharmacological effects in vivo, as well as influence of complex herb matrix. In addition, research is also needed to characterize the microbiotal deglycosylation and the subsequent aglycone metabolism by the host for more saponins, as well as the hepatobiliary transporter phenotyping for and the interaction with saponins. Furthermore, in vitro and in vivo studies of saponin-based herb-drug interactions are warranted for a broader range of saponins.
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Metabolite profiling and characterization for medicinal herbal remedies
Min Yang, Chunru Cheng, Junling Yang and De-an Guo
[Purchase Article] [PMID: 22292788 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00223]

Metabolisms of herbal remedies and their natural components, which play a critical role in support of medicine development, and clinical medication, are drastically different from those of designed drugs. The separation, isolation and identification of drug metabolites from complex endogenous matrices like urine, plasma and tissue extracts are extremely challenging. For herbal medicine studies, it is even more difficult due to the complex chemical composition. Usually, a combination of high performance liquid chromatography (HPLC) and mass spectrometry (MS) is proven to be a powerful analytical tool for screening and identifying drug metabolites. For suitable instruments, the quadrupole time-of-flight (Q-TOF), hybrid ion trap time-of-flight (IT-TOF), and orbitrap mass spectrometry could clearly enhance the efficiency in metabolite profiling compared to general triquadrupole (QQQ) and ion trap (IT) mass spectrometry technique. Due to the ability for unambiguous structure determination, nuclear magnetic resonance spectroscopy (NMR) is also coupled to HPLC for on-line analysis of metabolites. Capillary electrophoresis and gas chromatography are also optional methods. These techniques could provide abundant information from a wide variety of samples.

However, in many cases, preparations of metabolites are critical for further pharmacokinetics, pharmacologic, and toxic evaluation of the remedy. Therefore, accumulations of metabolites from the in vivo biological samples are essential. Biotransformation models are considered to be important complementary sources for preparation of drug metabolites. Fungi, plant cells, and a variety of enzymes were used to provide information for further in vivo testing.

This review focuses on the screening and identification of drug metabolites from herbal medicines.
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Herb-Drug Interactions and Mechanistic and Clinical Considerations
Shu-Ming He, Kevin B. Sneed, Xiao-Wu Chen, Chuanhai Cao and Shu-Feng Zhou
[Purchase Article] [PMID: 22292789 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00224]

Herbal medicines are often used in combination with conventional drugs, and this may give rise to the potential of harmful herb-drug interactions. This paper updates our knowledge on clinical herb-drug interactions with an emphasis of the mechanistic and clinical consideration. In silico, in vitro, animal and human studies are often used to predict and/or identify drug interactions with herbal remedies. To date, a number of clinically important herb-drug interactions have been reported, but many of them are from case reports and limited clinical observations. Common herbal medicines that interact with drugs include St John’s wort (Hypericum perforatum), ginkgo (Ginkgo biloba), ginger (Zingiber officinale), ginseng (Panax ginseng), and garlic (Allium sativum). For example, St John's wort significantly reduced the area under the plasma concentration-time curve (AUC) and blood concentrations of cyclosporine, midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline. The common drugs that interact with herbal medicines include warfarin, midazolam, digoxin, amitriptyline, indinavir, cyclosporine, tacrolimus and irinotecan. Herbal medicines may interact with drugs at the intestine, liver, kidneys, and targets of action. Importantly, many of these drugs have very narrow therapeutic indices. Most of them are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein (P-gp). The underlying mechanisms for most reported herb-drug interactions are not fully understood, and pharmacokinetic and/or pharmacodynamic mechanisms are implicated in many of these interactions. In particular, enzyme induction and inhibition may play an important role in the occurrence of some herb-drug interactions. Because herb-drug interactions can significantly affect circulating levels of drug and, hence, alter the clinical outcome, the identification of herb-drug interactions has important implications.
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Intestinal Absorption and Presystemic Elimination of Various Chemical Constituents Present in GBE50 Extract, a Standardized Extract of Ginkgo Biloba Leaves
Li Li, Yuansheng Zhao, Feifei Du, Junling Yang, Fang Xu, Wei Niu, Yaohui Ren and Chuan Li
[FULL-TEXT INQUIRY] [PMID: 22292790 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00225]

The nature and level of systemic exposure to the active herbal constituents will profoundly affect their effects at action sites, which is fundamental in understanding their roles in the overall beneficial effects of an herbal medicine. The objective of this study is to gain a full picture of the systemic exposure to various putatively active ginkgo constituents after p.o. administration of GBE50 extract, a standardized extract of Ginkgo biloba leaves, to rats and understanding of the relevant mechanisms governing the intestinal absorption and presystemic elimination. To define the ginkgo compounds to be studied, literature informatics-guided chemical profiling revealed that GBE50 extract contained 72 ginkgo constituents, including terpene lactones, flavonols, flavones, an isoflavone, biflavones, flavanols, and carboxylic acids, at levels ranging from 0.01 to 55.3 mg/g. Among the ginkgo constituent groups were the terpene lactones and the flavonols that were significantly measurable in plasma after p.o. administration of GBE50 extract to rats. The intestinal absorption of terpene lactones appeared to be dictated by their intermediate membrane permeability, while the influences of MDR-1- and MRP-2-mediated intestinal efflux and the presystemic metabolism and biliary excretion might be relatively limited. Because of their deglycosylation absent in the small intestine and relatively slow presystemic elimination, many intact flavonol glycosides appeared in the rat plasma albeit a limited extent of absorption. Colonic deglycosylation of the flavonol glycosides occurred and the glucuronides of flavonol aglycones were also measured in the plasma. Although some biflavones also had relatively high abundance in GBE50 extract, these ginkgo constituents were not measured in the rat plasma because of their poor solubility and poor permeability that hindered the intestinal absorption. The levels of the remaining ginkgo constituents in GBE50 extract were too low to be measured in the rat plasma. The current study enabled us to better understand the nature of systemic exposure to ginkgo compounds after p.o. administration of GBE50 extract and to more precisely implement multicomponent PK study of the extract.
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Metabolite profiling and Pharmacokinetics of Herbal Compounds Following Oral Administration of a Cardiovascular Multi-herb Medicine (Qishen Yiqi Pills) in rat
Yufeng Zhang, Peiying Shi, Hong Yao, Qing Shao and Xiaohui Fan
[FULL-TEXT INQUIRY] [PMID: 22292791 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00226]

Qishen yiqi pills (QY pills) are a type of standardized cardiovascular herbal medicine, which contain four component herbs, i.e., Astragalus membranaceus (Huangqi), Salvia miltiorrhiza (Danshen), Panax notoginseng (Sanqi), and Dalbergia odorifera (Jiangxiang). After oral administration of QY pills, the in vivo exposure types of each component herb in rats were first uncovered and identified according to a target-directed strategy based on hyphenated chromatography techniques. The dominated metabolites in urine, blood and bile were originated from flavonoids of Huangqi and monomer phenolic acids of Danshen; no metabolites but parent drugs of Sanqi ginsenosides, namely ginsenosides Rb1, Rd, Re and Rg1, notoginsenoside R1 and gypenoside XVII, were detected in rat urine and blood, and the 20(S)-protopanaxatriol type ginsenosides (NR1, GRe, GRg1) could also be excreted to bile; the high liposolubility of volatile oils from Jiangxiang restricted them to small intestine, liver and adipose tissues. The identification of metabolites in bio-samples was achieved by exact mass measurement and detailed fragmentation pathway analyses. In specific conditions, not only the types of phase II metabolism but also their conjugation positions could be determined by our established cleavage pathways, which lead to discriminate the phase II metabolites of protocatechualdehyde for the first time. Based on the metabolite study in rats, the 4 main compounds (tanshinol, astragaloside IV, GRb1 and GRg1) in QY pills were selected as pharmacokinetic markers. The PK results showed that their maximal concentrations in blood were obtained within one hour, much shorter than the reported values in single herbs. The rat exposure was proximately linear under the studied dosages from 1 to 6 g/kg.
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Aptamers as remarkable diagnostic and therapeutic agents in cancer treatment
Henri-Pierre Lassalle, Sophie Marchal, François Guillemin, Aurélie Reinhard and Lina Bezdetnaya
[FULL-TEXT INQUIRY] [PMID: 22380008 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00234]

Nucleic acid aptamers are molecules that are being used in a large number of biomedical applications. Aptamers have the properties to bind to a wide range of molecules with high specificity and affinity for their target. These properties together with their small size and their ease of synthesis make them very attractive and promising for targeting diseases and therapeutic applications. Aptamers can serve as cancer diagnostic tools by detecting specific biomarkers, circulating cancer cells or imaging diseased tissue. On the other hand, aptamers can be used as therapeutic agents due to their potential antagonist activity, or as targeting agents. Therefore, they can be designed to deliver antitumor molecules such as chemotherapeutic drugs, siRNA or photodynamic therapy sensitizers to diseased tissues. Attempts are also made to synthesize aptamers-targeted nanoplatforms capable to ferry cargo and load onto them both imaging and therapeutic functions creating so called nanotheragnostics agents. In the future, its seems likely that aptamers will play an important role in diagnosis and treatment of several pathologies including cancer.
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In vivo biodistribution, pharmacokinetics, and toxicology of carbon nanotubes
Kai Yang and Zhuang Liu
[FULL-TEXT INQUIRY] [PMID: 22380009 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00235]

Owing to their interesting physical and chemical properties, carbon nanotubes (CNTs) have attracted wide attentions in nanomedicine for applications in biological sensing, drug delivery, as well as biomedical imaging. The in vivo behaviors and toxicology of CNTs in biological systems, which are important fundamental questions, although have been intensively studied in recent years, remain to be clarified as distinctive results have been reported by various teams, confusing the scientific community as well as the public. In this article, we review the research on the in vivo behaviors of CNTs, and summarize the toxicity studies of CNTs in animals by different groups. Similar to other nanomaterials, the in vivo pharmacokinetics and biodistribution of CNTs are closely associated with their surface coatings. The excretion of CNTs from animals may happen via renal and fecal pathways, depending on the CNT surface chemistry, shape, and sizes. Regarding the toxicology of CNTs, which has been a debating topic for years, the administration routes, doses, and again the surface functionalization are critical to the in vivo toxicity of nanotubes. Much more efforts are still required to develop functional CNT bioconjugates with improved biocompatible coatings and controllable optimal sizes to achieve fast excretion and minimal toxicity, for various applications in biomedicine.
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Nano-based drug delivery system enhances the oral absorption of lipophilic drugs with extensive presystemic metabolism
Zhiwen Zhang, Fang Gao, Shijun Jiang, Li Ma and Yaping Li
[FULL-TEXT INQUIRY] [PMID: 22380010 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00236]

Oral administration remains the most preferred route for the treatment of many diseases due to its convenience and adaptability. However, the presystemic metabolism may be an important barrier that prevents lipophilic drugs from achieving their pharmacological effects following oral delivery. Nano-based drug delivery system provides an effective strategy to reduce the presystemic metabolism and increase the systemic exposure of lipophilic drugs. In this review, we described the physiological factors affecting the presystemic metabolism of lipophilic drugs, intestinal transport of nanosystems, strategy of nanosystems to avoid the presystemic metabolism, and the current application of various oral nanosystems including lipid and polymeric nanocarriers. The nano-based drug delivery system has a lot of potential for reducing the presystemic metabolism and enhancing the bioavailability of orally administrated lipophilic drugs.
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Dendrimers in cancer therapeutics and diagnosis
Rui Guo and Xiangyang Shi
[FULL-TEXT INQUIRY] [PMID: 22380011 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00237]

Dendrimers represent a class of monodispersed synthetic macromolecules with a well defined three-dimensional structure of nanometer dimension in which a series of layered branches regularly extend from a central core molecule. Due to their precise nanoscale sizes, well-defined branched structures, and various surface modifications, dendrimers have been extensively investigated in a wide range of applications in the biomedical field, particularly in the therapeutics and diagnosis of cancer. This article gives an overview of the recent advances of dendrimers and dendrimer-based hybrid nanoparticles for cancer therapeutics and diagnosis applications.
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Fluorescent Carbon Dots and Nanodiamonds for Biological Imaging: Preparation, Application, Pharmacokinetics and Toxicity
Jia-Hui Liu, Sheng-Tao Yang, Xinxin Chen and Haifang Wang
[FULL-TEXT INQUIRY] [PMID: 22380012 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00238]

The rapid advancement of nanotechnology has brought us some new types of fluorescent probes, which are indispensable for bioimaging in life sciences. Because of their innate biocompatibility, good resistance against photobleaching, long fluorescence lifetime and wide fluorescence spectral region, fluorescent carbon quantum dots (C-Dots) and nanosized diamonds (nanodiamonds, NDs) are gradually evolving into promising reagents for bioimaging. In this review, we summarize the recent achievements in fluorescent C-Dots and NDs with emphases on their preparation, properties, imaging application, pharmacokinetics and toxicity. Perspectives on further investigations and opportunities to develop C-Dots and NDs into the safer and more sensitive imaging probes for both living cells and animal models are discussed.
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Co-delivery strategies based on multifunctional nanocarriers for cancer therapy
Hao Chen, Ying Zhao, Hai Wang, Guangjun Nie and Kaihui Nan
[FULL-TEXT INQUIRY] [PMID: 22380013 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00239]

Chemotherapy is among the most common means for clinicians in the fight against various types of tumors. However, severe toxicity with undesirable toxic effects against normal tissues and cells significantly hinders the applications of these chemotherapeutic agents and leads to multiple complications for patients. Recent developments of nanotechnology-enabled drug delivery platforms allow simultaneous delivery of multiple chemotherapeutic agents to target different metabolic pathways of tumor cells, thus provide new opportunities for higher therapeutic efficacy and lower cytotoxicity. Furthermore, multifunctional nanocarriers can also deliver diagnostic agents, including MRI contrast agents and fluorescent probes, to achieve cancer diagnosis and therapy at the same time. This present review discusses the various aspects of current co-delivery strategies and emphasizes the need for novel designs of biocompatible and non or low toxic nanocarriers. Further studies on potential adverse effects of various nanocarriers are warranted.
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Toxicological Profile of Therapeutic Nanodelivery Systems
Luis M. Bimbo, Leena Peltonen, Jouni Hirvonen and Hélder A. Santos
[FULL-TEXT INQUIRY] [PMID: 22380014 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00240]

Several of the newly developed drug molecules show potent biological activity, but exhibit poor pharmacokinetic properties that may hinder their effective delivery to the intended site of action. In order to improve their pharmacological effect, these molecules can be associated with drug carriers in order to overcome these inherent difficulties. An ideal drug delivery agent requires therefore biocompatibility, improved solubility of a loaded drug or peptide, releasing of the payload at the absorption site and, at the same time, leaving undisturbed cell structure and function, and maintaining the physiological milieu. By taking advantage of the valuable properties of nanoscale delivery systems, such as increased surface area, improved solubility of hydrophobic drugs, possibility to encapsulate and protect drugs from degradation and reduced immunogenic potential and toxicological effect, new therapeutic options can be brought forth and improve the clinical arsenal for numerous diseases. The use of nanodelivery systems can even promote the re-investigation of pharmacokinetically less favourable, but biologically more active compounds. Although very promising, these systems may also encompass inherent toxicological issues, mainly due to their size and shape, physical interaction with cellular membranes and organelles, immunological reactions, long- or short-term tissue accumulation, and degradation products. Pharmaceutical nanodelivery systems, such as liposomes, polymeric nanoparticles, dendrimers and mesoporous silica and silicon based nanoparticles have shown great potential in pre-clinical applications and several of these nanosystems are even undergoing clinical trials. They have been found to combine drug delivery properties with an acceptable toxicological profile, which has made them prime candidates for several drug delivery approaches. This review aims to provide and correlate the toxicological studies with the drug delivery properties of the abovementioned nanodelivery systems in particular concerning uptake and accumulation as well as the critical aspects in each system regarding their optimal performance, while pointing to the most relevant references.
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Impacts of nanoparticles on cardiovascular diseases: modulating metabolism and function of endothelial cells
Jie Meng, Xian-da Yang, Lee Jia, Xing-Jie Liang and Chen Wang
[FULL-TEXT INQUIRY] [PMID: 22380015 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00241]

Endothelial cells have very important functions, one of which is their contribution to regulating molecule and nutrient exchanges between the blood and peripheral tissues. Dysfunction of endothelial cells plays an essential role in the progression of cardiovascular diseases (CVD) such as atherosclerosis and coronary heart disease. With the recent progress of nanotechnology, increasing numbers of studies have focused on the effects of nanoparticles on CVD. In this article, we review the biological characters of endothelial cells, evaluate the impacts of nanoparticles on the behavior and functions of endothelial cells, analyze advantages and disadvantages of various nanoparticles, and discuss potential applications of nanoparticles to CVD treatment.
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Nanoparticles improve biological functions of phthalocyanine photosensitizers used for photodynamic therapy
Xiao Jia and Lee Jia
[FULL-TEXT INQUIRY] [PMID: 22380016 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00242]

Photodynamic therapy (PDT) is a new technology using photodynamic effect for disease diagnosis and treatment. It is a two-step technique involving the uptake of a photosensitizer by cancer tissue followed by light irradiation that excites the photosensitizer to produce highly reactive oxygen species, the latter execute apoptosis of cancerous cells. As a second-generation of photosensitizers, phthalocyanine demonstrates higher absorption in the 650-800nm range and short tissue accumulation compared to their first generation. However, many potent phthalocyanine photosensitizers are hydrophobic and poorly water-soluble, which limit their therapeutic applications. As a result, advanced delivery systems and different strategies are called for to improve the effectiveness of PDT. Facts have proved that using nanoparticles as carries of photosensitizers is a very promising route. Nanoparticles have the potentials to increase photosensitizers’ aqueous solubility, bioavailability and stability, and deliver photosensitizers to the target tissues. This article reviewed the commonly-used nanoparticles, including colloid gold, quantum dots, paramagnetic nanoparticles, silica-based materials, polymer-based nanoparticles, as potential delivery systems for phthalocyanine photosensitizers, and summarized the improved biological functions of phthalocyanine photosensitizers in PDT.
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Fullerenes for Cancer Diagnosis and Therapy: Preparation, Biological and Clinical Perspectives
Zhiyun Chen, Ruoqing Mao and Ying Liu
[FULL-TEXT INQUIRY] [PMID: 22380017 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00243]

Cancer is a major public health problem in the world. There is a great need to apply novel technologies and drugs to revolutionize multiple aspects of cancer diagnosis and therapy. Advances in nanotechnology and nanomaterials have the potential to achieve the objective of early diagnosis and early therapy of cancer in the future. During the past few years, fullerene and its derivatives have been considered as some of the most promising nanomaterials because of their unique properties that enable a variety of medicinal applications. They can deliver drugs or small therapeutic molecules to the cancer cells. In this review, we will discuss how fullerene derivatives have been introduced into the field of cancer diagnosis and therapy. It will be highlighted that fullerene derivatives are used as anti-tumor drugs. Furthermore, preparation, characterization, pharmacokinetics and bio-distribution of fullerene and its derivatives reported in recent years will be summarized.
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Sex Differences In The Clearance Of Cyp3a4 Substrates: Exploring Possible Reasons For The Substrate Dependency And Lack Of Consensus
Manoranjenni Chetty, Donald Mattison and Amin Rostami-Hodjegan
[FULL-TEXT INQUIRY] [PMID: 22452452 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00244]

Sex differences in the clearance of substrates of Cytochrome P4503A (CYP3A4) have been reported frequently although there has been no consensus on reasons for variation in observations amongst drugs which are seemingly all dependent on this enzyme for their metabolism. Moreover, these observations could not be replicated in all studies even when investigating the same drugs. Differing study designs and inadequate power to identify the sex differences may explain the conflicting reports. The aim of the current study was to use in vitro data on a number of CYP3A4 substrates to develop mechanistic population pharmacokinetic models which are capable of integrating various attributes of drugs and estimating the statistical power of in vivo studies designed to discern sex differences in the clearance of CYP3A4 substrates. Midazolam, triazolam, alprazolam, nifedipine and zolpidem were selected as test substrates. These compounds are predominantly metabolised by CYP3A4, unaffected by p-glycoprotein and have abundant clinical studies which can be used for validation purposes. Simulated apparent clearance, obtained by use of the SIMCYP® Population-Based Simulator and in vitro in vivo extrapolation (IVIVE) techniques, was compared in males and females after correcting for weight (CL/wt) in 1560 trials. Results suggested that about 105 subjects per study are required for an 80% probability of identifying a higher CL/wt in females with alprazolam, while the corresponding numbers for a similar power were 120, about 150 and 300 for nifedipine, triazolam and oral midazolam, respectively. The results were consistent with outcomes in published clinical studies and support the view that many of the published studies have inadequate power to detect these sex differences in drug clearance, thereby contributing to the lack of consensus on this subject.
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Physiologically-based Pharmacokinetic (PBPK) Models for Assessing the Kinetics of Xenobiotics during Pregnancy: Achievements and Shortcomings
G. Lu, K. Abduljalil, M. Jamei, T.N. Johnson, H. Soltani and A. Rostami-Hodjegan
[FULL-TEXT INQUIRY] [PMID: 22452453 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00245]

The physiological changes that occur in the maternal body and the placental-foetal unit during pregnancy influence the absorption, distribution, metabolism, and excretion (ADME) of xenobiotics. These include drugs that are prescribed for therapeutic reasons or chemicals to which women are exposed unintentionally from the surrounding environment. The pregnancy physiologically-based pharmacokinetic (p-PBPK) models developed for theoretical assessment of the kinetics of xenobiotics during pregnancy should take into account all the dynamic changes of the maternal and embryonic/foetal physiological functions.

A number of p-PBPK models have been reported for pregnant animals and humans in the past 3 decades which have mainly been applied in the risk assessment of various environmental chemicals. The purpose of this review is to critically evaluate the current state of the art in p-PBPK modelling and to recommend potential steps that could be taken to improve model development and its application particularly in drug discovery and development for pregnant women, with potential implications for optimal drug treatment in pregnancy.

The pregnancy-induced changes in physiology and pharmacokinetics, including metabolism, are reviewed to illustrate the basic alterations essential for pregnancy model development.  A systemic search of the literature for existing p-PBPK models is carried out and the model structures, governing equations, methods of modelling growth, model validation/verification as well as model applications are highlighted. This review discusses benefits and limitations of the reported p-PBPK models so far and suggests areas for model improvement. The need for establishing databases on the system-related (biological, anatomical and physiological) and drug-related (phys-chem, affinity to enzymes and transpoorters) parameters for healthy and unhealthy pregnancies is particularly emphasized.
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Pharmacotherapy in neonatal and pediatric extracorporeal membrane oxygenation (ECMO)
E.D. Wildschut, M.J Ahsman, R.J. Houmes, P. Pokorna, S.N. de Wildt, R.A.A. Mathot and D. Tibboel 
[FULL-TEXT INQUIRY] [PMID: 22452454 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00246]

ECMO support is an established life saving therapy for potentially reversible respiratory and/or cardiac failure. Improvement of outcome depends on effective treatment of the primary diagnosis and complications. Adequate drug therapy is important in reaching these goals. Pharmacokinetic and pharmacodynamic data in neonates and older children on ECMO are sparse. Most studies show altered volume of distribution and clearance for the drugs studied. This article gives an overview of the available PK and PD studies in neonates and children on ECMO, suggests possible mechanisms of altered PK and PD and identifies areas of interest for further research.
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Ontogeny of Hepatic Glucuronidation; Methods and Results
Elke Henriëtte Josephina Krekels, Meindert Danhof and Dick Tibboel
[FULL-TEXT INQUIRY] [PMID: 22452455 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00247]

The onset and maturation, or so-called ontogeny, of hepatic glucuronidation is important for the clearance of a number of drugs in children. The current review discusses methods for studying the ontogeny of liver enzyme systems and specifically focuses on the results obtained with these methods for uridine 5’-diphosphate glucuronosyltransferases (UGTs). The number of contributing components in the biological system increases in going from mRNA transcription, to enzyme expression, in vitro enzyme activity, and in vivo glucuronidation clearance. This may result in different conclusions on UGT ontogeny when different methods are used. Various metrics to quantify glucuronidation activity, like linear or allometric scaling based on bodyweight, further disperse the conclusions on UGT ontogeny. Generally, it can be concluded that the onset of UGT expression and activity occurs after 20 weeks of gestation with a boost in expression and activity occurring in the first weeks of life. Maturation rates vary between the UGTs, but may well extend beyond the age of two years. Compared to adults, absolute doses of drugs eliminated via glucuronidation should be reduced in children. However, since the UGT isoenzymes mature differently, since substrate specificities are overlapping and since many external factors influence drug glucuronidation, it is not possible to derive general dosing recommendations for the pediatric population for these drugs. This can be improved by obtaining system specific information on each UGT isoenzyme on the basis of validated in vivo models that describe the ontogeny of glucuronidation and the influence of other patient characteristics like genetic polymorphisms and co-morbidities on the (intrinsic) clearance of isoenzyme specific probe drugs.
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Growing up with midazolam in the neonatal and pediatric intensive care
Eleonora L. Swart, Pauline R. Slort and Frans B. Plötz
[FULL-TEXT INQUIRY] [PMID: 22452456 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00248]

A variety of developmental changes is of influence on the pharmacokinetics and pharmacodynamics of midazolam in neonatal and pediatric intensive care patients. However, dosing regimens in children are based upon rather empirical extrapolations from the dosing regimens in adults. Based on current available studies it appears that with the rising of age, the pharmacokinetics of intravenously administered midazolam alter, resulting in a shorter half-life due to a higher hepatic clearance in older children as compared to newborn. Also, with the rising of age, the pharmacodynamics of intravenously administered midazolam may alter due to a decrease in density of receptors, possibly leading to a decreased clinical response. These findings implicate opposite effects and it is uncertain which of these effects are predominant. In conclusion, there is a large interindividual variability in the response to midazolam in children, which may be caused by differences in pharmacokinetics and pharmacodynamics. Both are subject to considerable developmental changes. It remains remarkable that high-quality evidence to support the use of midazolam for continuous sedation in the neonatal and pediatric intensive care setting is lacking.
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Pharmacokinetic Considerations of Perinatal Antiretroviral Therapy
Natella Y. Rakhmanina, Sahera Dirajlal-Fargo, Edmund V. Capparelli and Mark Mirochnik
[Purchase Article] [PMID: 22452457 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00249]

Antiretroviral therapy (ART) in pregnant women represents a unique combination of therapy and prophylaxis of HIV infection. Until the global epidemic of HIV and the discovery of efficient prevention of perinatal transmission through ART, the world has not witnessed a pharmacologic intervention of such a scale during pregnancy and delivery. The use of ART in pregnancy creates unique challenges in delivering therapeutic agents, targeting the HIV virus in both the pregnant woman and her unborn child, throughout dramatic changes in their physiologic state. With an increased complexity of perinatal ART and the introduction of novel agents into clinical practice, a better understanding of the pharmacokinetics (PK) and pharmacodynamics of ARV drugs is crucial for the safe and most effective use of ARV drugs in women during pregnancy and infants in the first months of life. While PK studies are already difficult to perform during pregnancy, they are particularly challenging in women with HIV infection due to multiple social, economic and cultural constrains. In this paper we provide an overview of published studies of ART disposition during pregnancy, labor, breastfeeding and in the newborn infant after delivery.
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Pharmacogenetics of opioids for the treatment of acute maternal pain during pregnancy and lactation
Parvaz Madadi, Denise Avard and Gideon Koren
[FULL-TEXT INQUIRY] [PMID: 22452458 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00250]

There have been an increasing number of clinical studies investigating the relationship between interindividual genetic variability and the safety and efficacy of opioid analgesics.  Despite the widespread use of opioids in pregnant and lactating women for the treatment of acute pain, few studies have investigated the interplay of genetic factors and pregnancy-related physiological alterations in relation to opioid metabolism and response.  Some interesting avenues of research require further pursuit- including evidence of cytochrome P450 2D6 (CYP2D6) induction during pregnancy and its effect on the generation of the active opioid metabolites morphine, oxymorphone, O-desmethyltramadol, and hydromorphone following the administration of codeine, oxycodone, tramadol, and hydrocodone respectively.  Studies investigating the duration of maternal CYP2D6 induction after delivery are also needed to shed light on genotype to phenotype correlations in breastfeeding mothers using opioid analgesics in the postpartum period.
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The role of ABC and SLC transporters in the pharmacokinetics of dietary and herbal phytochemicals and their interactions with xenobiotics
Yan Li, Jun Lu and James W. Paxton
[FULL-TEXT INQUIRY] [PMID: 22475331 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00252]

There is accumulating evidence that many compounds, known as phytochemicals (PCs), which are derived from dietary plants and herbs, may have a role in combating a number of chronic diseases. Despite many in vitro studies elucidating the mechanism(s) of action of various PCs, there are still reservations with regard to their health benefits in vivo, particularly as there is a paucity of research on their oral bioavailability, their pharmacokinetics, and the concentrations achieved at their site(s) of action. Recently various transporters, including the ATP-binding cassette (ABC) and the solute carrier (SLC) transporters, have been cloned and functional analyses have suggested that they play significant roles in the absorption and disposition of most drugs and PCs. While some SLC transporters facilitate absorption of PCs into the systemic circulation, various efflux pumps, including the ABC transporters, actively transport the PC back into the gastro-intestinal (GI) lumen, thus preventing further penetration into the body. Some ABC transporters also act in concert with Phase 1 and 2 metabolizing enzymes as a defensive barrier in the intestines and liver. If the PC overcomes the defence mechanisms of the gut and the liver, it will enter the systemic circulation and be distributed to the other organs of the body and possible site(s) of action. PCs can usually pass with ease through the pores of the capillaries of organs such as the heart and lungs, but with difficulty into pharmacological sanctuaries, such as the brain, testis, or foetus. Such sanctuaries contain a number of efflux transporters in their protective membrane, which restrict the penetration of xenobiotics, including PCs.  The ABC and SLC transporters are also abundantly expressed in the liver and kidney and regulate the excretion of many compounds, including PCs and their metabolites. It is also becoming apparent that there is a complex interplay between various PCs and their ability to modulate the activity of these transporters involved in the processes of absorption, metabolism, distribution and excretion, which control the extent of xenobiotic exposure in the body. This review describes the importance of the ABC and SLC transporters in the pharmacokinetics of dietary and herbal PCs, and their interactions with other xenobiotics.
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Roles of UDP-glucuronosyltransferases in Phytochemical Metabolism of Herbal Medicines and the Associated Herb-drug Interactions
Li Li, Haihong Hu, Siyun Xu, Quan Zhou and Su Zeng
[FULL-TEXT INQUIRY] [PMID: 22475332 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00253]

UDP-glucuronosyltransferases (UGTs) play important roles in the disposition of many drugs and xenobiotics. Herbal medicine, an important group of multicomponent therapeutics, is widely and increasingly used. Drug metabolism of herbal medicine mediated by cytochrome P450s has been extensively studied; however, herbal medicine metabolism mediated by UGTs has not been adequately investigated. Thus, it is necessary to evaluate current evidences on the glucuronidation of herbal medicines by UGTs. In this review, the research advances of the potential for commonly used herbal medicines as UGT substrate and modulator are summarized. In addition, the herb-drug interactions associated with UGTs are also discussed.
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Interactions between Phytochemicals from Traditional Chinese Medicines and Human Cytochrome P450 Enzymes
Jing-Jing Wu, Chun-Zhi Ai, Yong Liu, Yan-Yan Zhang, Miao Jiang and Ai-Ping Lv  Ling Yang
[FULL-TEXT INQUIRY] [PMID: 22475333 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00254]

The traditional Chinese medicine (TCM) formula with fixed combinations replies on "principal, assistant, complement and mediating guide" and fuzzy mathematic quantitative law, leading to more challenge that would be faced for the identification of active ingredients. Transformation and metabolic studies involved phase I drug-metabolizing enzyme system cytochrome P450 (CYP) might potentially alleviate a lot for this challenge. The pharmacological effects can hardly attribute to one active ingredient in TCMs, but integrated effects resulted from combined actions taken by multi–ingredients. However, only in the condition of long-term administration, can most ingredients take their actions, which would result in the prolonged exposure of herbs in vivo. So interactions between herbal compounds and CYPs appeared to be inevitable. Nevertheless, unlike western drugs, experimental determination of the absorption and disposition properties is not very common for TCMs. Moreover, using TCM as injections is an innovation aiming to improve efficiency in extensive clinical use in Mainland China. However, cases have been reported in recent years in terms of adverse drug reaction (ADR) mainly concerning allergic reactions, such as ShenMai injection, QingKaiLing injection, et al, which attract close attention on the legal responsibilities for TCM approval. Lack of the information about the ADME characteristics, especially the metabolic stability and interactional potentials between CYPs and herbs, increases the ADR occurrence of TCMs. In this article, we review the top herbs used in TCM prescriptions and fixed combinations by their usable frequency, and summarize the current understanding of the ability of their phytochemicals ingredients to act as substrates, inhibitors or inducers for human CYP enzymes, by which the key role of CYP enzymes on the herb disposition and toxicity is highlighted. The interaction potential between herbal phytochemicals and CYP enzymes dominates the target exposure, further help elucidate the herbal pharmacological basis, assess the individual toxic risk of herbal remedies and gain mechanistic insight into herb–drug interactions (HDIs).
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Drug metabolism and pharmacokinetics of nanodrugs from Chinese medicines and natural products
Chang-Xiao Liu, Duan-Yun Si, Xue-Feng Xiao, Xin He and Ya-Zhuo Li
[FULL-TEXT INQUIRY] [PMID: 22475334 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00255]

Over the past few years, nanoscale Chinese medicine has become one of focus in modern Chinese medicine research. There is an increasing need for a more systematic study of the basic issues involved in traditional Chinese medicine and a more active participation of researchers in the application area of nanoscale traditional Chinese drugs. In this review, author analyzed the current applications of nanotechnology in research and development of drugs from natural products and herbal medicines involving traditional Chinese medicines, and also discussed the bio-medicinal evaluation issues on ADME including bio-distribution and metabolism of nanodrugs. Author noted that the facing great challenges in nanodrugs from herb drugs and natural products are the follows: (1) the first challenge is to prepare nanodrug delivery system and quantitatively evaluate the therapeutic effects and safety; (2) the second challenge is to clarify the concrete metabolism course; and (3) the third challenge is to study the pharmacokinetics of nanodrugs.
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Pharmacokinetics-Pharmacology Disconnection of Herbal Medicines and Its Potential Solutions with Cellular Pharmacokinetic-Pharmacodynamic Strategy
Jingwei Zhang, Fang Zhou, Meng Lu, Wei Ji, Fang Niu, Weibin Zha,  Xiaolan Wu, Haiping Hao and Guangji Wang
[FULL-TEXT INQUIRY] [PMID: 22475335 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00256]

Recently, there is a global trend of using herbal medicines to treat various chronic diseases and promote health. But the controversy over the safety and efficacy of herbal medicines is a focus of attention, primarily because of the many unknown and unrevealed natures of herbal medicines, which strongly restricts their application and development. Pharmacokinetics is a bridge linking the herbal medicines and their pharmacological responses. It is assumed in traditional pharmacokinetics that an excellent drug should have appropriate pharmacokinetic behaviours and its pharmacological effect is related with plasma drug concentrations. However, most herbal medicines exhibit excellent pharmacological responses despite poor pharmacokinetic behaviours. As most drugs are intracellular-targeted, we put forward cellular pharmacokinetic-pharmacodynamic strategy, which is focused on the intracellular fate of drugs. This strategy could partially explain the marked pharmacological activities of herbal medicines from their intracellular pharmacokinetic behaviours, rather than their plasma concentrations. It is a helpful complementarity to traditional pharmacokinetics, and takes a potential role in the research and development of new herb-origined drugs. In this review, the pharmacokinetics-pharmacology disconnections of herbal medicines (such as ginseng, berberine and danshen) are retrospected. Then our proposed cellular pharmacokinetic-pharmacodynamic strategy, its characteristics, as well as its research procedures are described, followed by the subcellular distributions of drug transporters and metabolic enzymes which are the determinants of cellular pharmacokinetics-pharmacodynamics. Finally, our successful applications of cellular pharmacokinetic-pharmacodynamic strategy in elucidating ginsenoside Rh2 as an adjuvant agent and tanshinone IIA as an anticancer agent are illustrated.
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De-Risking Bio-therapeutics for Possible Drug Interactions Using Cryopreserved Human Hepatocytes
Shannon Dallas, Carlo Sensenhauser, Ameesha Batheja, Monica Singer, Maria Markowska, Cindy Zakszewski, Rao N.V.S. Mamidi, Michael McMillian, Chao Han, Honghui Zhou and Jose Silva
[FULL-TEXT INQUIRY] [PMID: 22475265 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00257]

Inflammatory diseases such as rheumatoid arthritis and psoriasis are characterized by increases in circulating cytokines, which play an important role in modulation of the disease state. Several marketed bio-therapeutics target cytokines and act as effective treatment strategies. Previous in-vitro and in-vivo studies have suggested that cytokines may have both direct and indirect effects on drug metabolizing enzyme levels in the liver. Few studies have characterized models to evaluate the risk of potential drug interactions that might be mediated by changes in cytokine levels. In the present studies the potential of three cytokines (IL-2, IL-6 and TNF-α) to modulate gene expression and activity of the major human cytochrome P450 (CYP) enzymes (CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A4) in cryopreserved human hepatocytes (CHH) was investigated. Significant decreases in the activity of all 6 CYP isoforms occurred in hepatocytes incubated with TNF-α or IL-6 (17-85% and 22-76% of untreated control values, respectively). TNF-α down-regulated the gene expression of CYP1A2, 2D6 and 3A4 only, whereas IL-6 down-regulated gene expression of all of the tested CYP isoforms except 2D6. IL-2 had only mild effects on CYP activity and mRNA levels of examined isoforms. In CHH exposed to TNF-α, changes in CYP activity were not always paralleled by gene expression alterations for three of the examined CYP isoforms. These studies highlight several potential pitfalls in using isolated human hepatocytes for determination of drug interactions by bio-therapeutics including lack of correlation of mRNA and activity measurements for some CYP isoforms when using single time point determinations, and appropriateness of the model for indirect acting cytokine and cytokine modulators.
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Drug Interaction Potential of Trastuzumab Emtansine Combined With Pertuzumab in Patients With HER2-Positive Metastatic Breast Cancer
Dan Lu, Howard A Burris III, Bei Wang, E Claire Dees, Javier Cortes, Amita Joshi, Manish Gupta, Joo-Hee Yi, Yu-Waye Chu, Ted Shih, Liang Fang and Sandhya Girish
[FULL-TEXT INQUIRY] [PMID: 22475266 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00258]

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprised of trastuzumab and the cytotoxic agent DM1 (derivative of maytansine) linked by a stable linker N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC). T-DM1 targets an epitope located at subdomain IV of human epidermal growth factor receptor 2 (HER2). Pertuzumab is a monoclonal antibody that targets an epitope located at subdomain II of HER2, distinct from the epitope recognized by T-DM1. The pharmacokinetics (PK), safety, and efficacy of T-DM1 combined with pertuzumab were studied in a phase 1b/2 trial in 67 patients with HER2-positive, locally advanced or metastatic breast cancer (MBC). The therapeutic protein-drug interaction (TP-DI) potential of T-DM1 plus pertuzumab was evaluated. The PK of T-DM1–related analytes and pertuzumab were compared with historical PK data. The results show that the exposure of T-DM1 and DM1, as estimated by noncompartmental analyses, was comparable with that reported by historical single-agent studies in patients with HER2-positive MBC. T-DM1 clearance and volume of distribution in the central compartment, as estimated by population PK analysis, were also comparable between this study and historical single-agent studies in patients with HER2-positive MBC. Summary statistics of pertuzumab trough and maximal exposure (concentrations at predose and 15–30 minutes after the end of infusion at cycle 1 and at steady state) were similar with those observed in a representative historical single-agent study with the same dosing regimen. The visual predictive check plot by population simulation further confirmed that T-DM1 did not alter pertuzumab PK. Based on these data and the PK and pharmacodynamic properties of T-DM1 and pertuzumab, the risk of TP-DI appears to be low when T-DM1 and pertuzumab are given together.
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Effects of Interleukin 1β (IL-1β) and IL-1β /Interleukin 6 (IL-6) Combinations on
Drug Metabolizing Enzymes in Human Hepatocyte Culture
Leslie J. Dickmann, Sonal K. Patel, Larry C. Wienkers and J. Greg Slatter
[Purchase Article] [PMID: 22475267 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00259]

Exposure to cytokines can down-regulate hepatic cytochrome P450 enzymes. Accordingly, relief of inflammation by cytokinetargeted drug therapy has the potential to up-regulate cytochrome P450s and thereby increase clearance of co-administered drugs. This study examined the effects of the inflammatory cytokine, interleukin 1β (IL-1β), and IL-1β /interleukin 6 (IL-6) combinations on drug metabolizing enzymes in human hepatocyte culture. Treatment of hepatocytes with IL-1β revealed suppression of mRNA expression of several clinically important cytochrome P450 isoenzymes, with EC50 values that differed by isoenzyme. Suppression of CYP1A2 activity by IL-1β could not be measured in 3 of 5 donors due to lack of response and in the two remaining donors the average EC50 was 450 pg/mL. CYP3A activity had an EC50 of suppression of 416 ± 454 pg/mL. Measurable EC50s were obtained for all 5 donors for CYP2C8, 3A4, 3A5, 4A11 and IL-6R mRNA with fold differences which varied between 9.5-fold (CYP2C8) to 109-fold (CYP4A11). When hepatocytes were treated with IL-1β and IL-6 in combination at concentrations which ranged from 1-100 pg/mL, IL-6 was the main determinant of increases in acute phase response marker mRNA and of decreases in CYP3A4 mRNA. There was no synergy between IL-1β and IL-6 in the regulation of cytochrome P450 mRNA when dosed in combination, although the effects of the two cytokines in combination were additive in certain instances. These data indicate that IL-1β and IL-6 both suppress cytochrome P450 mRNA and enzyme levels in vitro and that, at similar physiologically-relevant concentrations in vitro, IL-6 is more potent than IL-1β.
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Animal Models for Evaluation of Drug-Drug Interaction Potential of Biotherapeutics
Eugenia Kraynov, Martin E. Dowty, Odette A. Fahmi and Owen Fields
[FULL-TEXT INQUIRY] [PMID: 22475268 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00260]

The increased development and availability of therapeutic proteins (TP) requires a greater understanding of drug-drug interactions (DDI) in a poly-pharmacy environment. Medications that are likely co-administered in various patient populations have to be considered in the context of direct pharmacokinetic properties of co-administered drugs as well as indirect effects due to disease modification. Anticipating and managing drug-drug interactions are an important part of the clinical development of both small and large molecules. Animal models may provide useful information in this regard with respect to human translatability. However, very limited work has been done to better understand the value of animal models for predicting the potential for TP DDI. Potential DDI mechanisms of TPs, with the exception of cytokine-mediated alteration of drug metabolizing enzymes and transporters, are less well known. This review discusses the potential value and specific challenges in the use of animal models for TP DDI evaluation.
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Catabolic Fate and Pharmacokinetic Characterization of Trastuzumab Emtansine T-D<1: An Emphasis on Preclinical and Clinical Catabolism
Ben-Quan Shen, Daniela Bumbaca, Ola Saad, Qin Yue, Cinthia V. Pastuskovas, S. Cyrus Khojasteh, Jay Tibbitts, Surinder Kaur, Bei Wang, Yu-Waye Chu, Patricia M LoRusso and Sandhya Girish
[Purchase Article] [PMID: 22475269 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00261]

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in clinical development for the treatment of human epidermal growth factor receptor 2 (HER2)-positive cancers. Herein, we describe a series of studies to assess T-DM1 absorption, distribution, metabolism, and excretion (ADME) in rats as well as to assess human exposure to T-DM1 catabolites. Following administration of unlabeled and radiolabeled T-DM1 in female Sprague Dawley rats as a single dose, plasma, urine, bile and feces were assessed for mass balance, profiling and identification of catabolites. In rats, the major circulating species in plasma was T-DM1, while DM1 concentrations were low (1.08 to 15.6 ng/mL). The major catabolites found circulating in rat plasma were DM1, [N-maleimidomethyl] cyclohexane-1- carboxylate-DM1 (MCC-DM1), and Lysine-MCC-DM1. These catabolites identified in rats were also detected in plasma samples from patients with HER2-positive metastatic breast cancer who received single-agent T-DM1 (3.6 mg/kg every 3 weeks) in a phase 2 clinical study. There was no evidence of tissue accumulation in rats or catabolite accumulation in human plasma following multiple dosing. In rats, T-DM1 was distributed nonspecifically to the organs without accumulation. The major pathway of DM1-containing catabolite elimination in rats was the fecal/biliary route, with up to 80% of radioactivity recovered in the feces and 50% in the bile. The rat T-DM1 ADME profile is likely similar to the human profile, although there may be differences since trastuzumab does not bind the rat HER2- like receptor. Further research is necessary to more fully understand the T-DM1 ADME profile in humans.
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Effects of Culture Duration on Gene Expression of P450 Isoforms, Uptake and Efflux Transporters in Primary Hepatocytes Cultured in the Absence and Presence of Interleukin- 6: Implications for Experimental Design for the Evaluation of Downregulatory Effects of Biotherapeutics
Qian Yang, Utkarsh Doshi, Nicole Li and Albert P. Li
[Purchase Article] [PMID: 22475270 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00262]

We report here a comprehensive evaluation of the effects of culture duration on the gene expression of P450 isoforms, uptake transporters and efflux transporter in human hepatocyte cultured in the absence and presence of the prototypical proinflammatory cytokine, interleukin-6 (IL-6). Primary collagen-matrigel sandwich cultures of human hepatocytes were cultured in supplemented William’s E medium containing 0, 0.1, 0.5 and 5 ng/mL of IL-6 for the time periods of 2, 6, 12, 24 and 48 hrs. Real-time PCR was performed to quantify gene expression of acute phase proteins (suppressor of cytokine signaling 3 (SOCS-3), c-reactive protein (CRP) and lipopolysaccharide (LPS)-binding proteins (LBP)); P450 isoforms (CYPs 1A2, 2B6, 2C8, 2C9, 2D6, 3A4, and 3A5), uptake transporters (SLC10A1, SLC22A1, SLC22A7, SLCO1B1, SLCO1B3, SLCO2B1) and efflux transporters (ABCB1, ABCB11, ABCC2, ABCC3, ABCC4, ABCG2). SOCS-3, CRP, and LBP were extensively induced by IL-6, with maximal induction observed at 2 (SOCS-3) and 12 hrs (CRP; LBP), demonstrating that the cultured human hepatocytes responded to IL-6 treatment. In the untreated group (control), gene expression of P450 isoforms and uptake transporters decreased while efflux transporters remained relatively stable or increased with cultured duration. IL-6 predominantly caused down regulations of the genes studied, with the most significant changes observed at different treatment durations, apparently related to the stability of the basal levels of gene expression. For instance, for genes with unstable expression, which would decrease rapidly in culture (e.g CYP3A4), the most definitive down regulatory effects were observed at a relatively early time point (e.g. 12 hrs). In contrast, a longer treatment duration (e.g. 48 hrs) was required for genes with relatively stable expression levels in culture (e.g. ABCB1). Based on our findings, evaluation of multiple treatment durations rather than single treatment duration is recommended for the evaluation of biotherapeutics in cultured human hepatocytes where down regulation is expected.
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Disposition and Interaction of Biotherapeutics in Pediatric Populations
Souzan Yanni
[FULL-TEXT INQUIRY] [PMID: 22475271 PubMed - indexed for MEDLINE] [BSP/CDM/E-Pub/00263]

Human development of an individual from a fertilized ovum to maturity alters the body anatomy and physiology. Changes of size and function, from birth onwards, cause significant alterations in the pharmacokinetics (PK) of drugs and subsequently their response pharmacodynamics (PD) in infants and children from those in adults. During the last three decades, hundreds of mechanistic and clinical pharmacology studies have been conducted to investigate the age-mediated changes of absorption, distribution, metabolism and excretion processes of drugs, which subsequently affect the pharmacology response and the safety in pediatric patients compared to adults. The practice of determining pediatric dose based on simplistic scaling of an adult dose assuming linear relationship between postnatal age and body weight or surface area that may lead to under prediction of therapeutic dose or over prediction of the dose is now under scrutiny. By understanding the disposition mechanism of therapeutic agents thoroughly, their potential drug interactions and their PK/PD relationships can be better determined in pediatric populations. As such, dosing regimens can be estimated based on actual clearance and exposure and not just by simplistic scaling of an adult dose. Accurate prediction of clearance in pediatrics is so critical that extensive translational research is warranted to improve our ability to estimate safe and efficacious doses in different pediatric populations from retrospective clinical studies in adults.

Biotherapeutics, proteins and peptides-based drugs, generally depend on absorption (A), distribution (D), metabolism (M), and excretion (E) in their disposition as small molecules, but the underlying mechanisms and potential drug interaction propensity can be very different.

In this article, the factors that alter pediatric and adult PK parameters are compared, and pediatric and adult PK parameters and potential drug interactions for selected biotherapeutics are summarized.

Moreover, challenges of studying therapeutic proteins and peptides in pediatrics are discussed.
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Function and regulation of the Cyp2a5/CYP2A6 genes in response to toxic insults in the liver
A’edah Abu-Bakar, Jukka Hakkola, Risto Juvonen, Minna Rahnasto-Rilla, Hannu Raunio and Matti A Lang
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00266]

The mouse hepatic cytochrome P450 (CYP) 2A5 and its human orthologue CYP2A6 catalyse the metabolism of a number of drugs and toxins, such as halothane and aflatoxin B1. The enzymes are named “Coumarin 7–hydroxylase” and “Nicotine Hydroxylase”, respectively, by virtue of their high affinity and specific activity towards these compounds. Bilirubin, the breakdown product of haem, has been suggested to be the endogenous substrate for both enzymes. Uniquely, CYP2A5 and CYP2A6 are induced during pathological conditions associated with liver injury when the function of most other CYP enzymes is compromised, which suggests an exceptional mode of regulation of the corresponding genes. Regulation of these genes is indeed complex where the promoters interact with multiple stress-activated transcription factors. The Cyp2a5 promoter contains a “stress-responding” cluster of binding motifs, which interact with major mediators of toxic insults including nuclear factor-E2 p45-related factor 2 (Nrf2) and aryl hydrocarbon receptor (AhR). These interactions are crucial in the up-regulation of the genes under stress conditions. Additionally, elevated transcription is also achieved through mRNA stabilization mediated by interaction of the stress activated hnRNP A1 with the 3’UTR of the CYP2A5/CYP2A6 mRNA. The up-regulation via enhanced transcription combined with mRNA stabilisation, as seen in some of the stress situations, leads to a particularly strong, fast and persistent response. This review brings together knowledge obtained from studies in our laboratories and others’ on regulation of Cyp2a5/CYP2A6 genes in response to toxic insults and toxicological significance of their catalytic activities that may provide clues to a functional role of the enzymes in relation to liver toxicity.
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Evaluation of the Physicochemical and Biopharmaceutical properties of Fluoro-Indomethacin
Michela M. Mori, Anu J. Airaksinen, Jouni T. Hirvonen, Hélder A. Santos and Carla M. Caramella
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00267]

Drug nanocarriers have shown great potential in therapy and as diagnostic probes, such as in imaging of cancer and inflammation. Imaging can be applied to localize the carrier or the drug itself in the body and/or tissues. In this particular case it is important that drug molecules have the characteristics for possible detection, e.g. after modification with positron emission tomography (PET) compliant radioisotopes, without affecting their pharmacological behaviour. In order to easily and efficiently follow the ADME profile of the drug after loaded into nanocarriers, the drug can be radiolabelled with, e.g. ¹⁸F-label, in order to assess its biodistribution after enteral and parenteral administration in rats. However, this is only possible if the derivative compound behaves similarly to the parent drug compound. In this study, indomethacin (a poorly water-soluble drug) was chosen as a model compound and aimed to evaluate the physicochemical and biopharmaceutical properties of an analogue of indomethacin (IMC), fluoro-indomethacin (F-IMC). Although some of the physicochemical and biopharmaceutical properties of IMC are already known, in order to establish a feasible comparison between IMC and F-IMC, the behaviour of the former was also investigated in the same conditions as for F-IMC. In this context, both IMC and F-IMC were thermally and morphologically studied. Furthermore, the following properties were also studied for both compounds: pK_a and log P, solubility and dissolution profiles at physiological pH values, and toxicity at different concentrations in Caco-2 cells. Finally, the transport across Caco-2 monolayers of the IMC and F-IMC at physiological pH range was also investigated. The results obtained showed similar values in pK_a-logP, solubility, dissolution, cytotoxicity, and permeability for both compounds. Thus, there might be strong evidence that both IMC and F-IMC should have a similar ADME behaviour and profiles in vivo. The results provide fundamental tools and ideas for further research with nanocarriers of ¹⁸F-IMC.
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Improving Oral Absorption via Drug-Loaded Nanocarriers: Absorption Mechanisms, Intestinal Models and Rational Fabrication
Mohammad-Ali Shahbazi and Hélder A. Santos
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00268]

Although it is acknowledged that the main impediment of orally administered therapeutic agents is their extensive and changeable pre-systemic metabolism, low absorption and instability in harsh environment of gastrointestinal (GI) tract are also mainly influential factors, resulting into inadequate and erratic bioavailability. To overcome these shortcomings, nanotechnology has been offered new promising strategies to prevent and treat a wide variety of diseases by employing different oral drug-carrier structures capable to enhance therapeutic effects and minimize the toxicity of healthy organs or cells. This review, in general, elucidates some considerable features of in vitro oral drug delivery in three different parts. The first one summarizes the main challenges for oral drug delivery and available absorption mechanisms. The second part embodies an in-depth discussion on the role of intestinal absorption models used to predict permeability, cellular uptake or even toxicity of nanoparticles, resulting into the design of nanocarriers with optimum efficacy for oral delivery.

The third section of the literature is devoted, more particularly, to nanocarriers developed for oral absorption in the past few years, including the behaviour of nanovehicles upon oral administration with respect to membrane permeability, retention properties and stability, as well as methods which may lengthen residence time in the GI environment or improve drug absorption.
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Precision-cut intestinal slices as in vitro tool for studies on drug metabolism
Geny M.M. Groothuis and Inge A.M. de Graaf
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00269]

The role of the intestine in drug metabolism has long been underestimated as a consequence of the technical difficulty to discern the role of intestine from that of the liver in in vivo experiments and of the lack of in vitro models that are sufficiently viable and fully representing the physiology and anatomy of the intestine. Recently the precision-cut slice model, which is widely used for liver and kidney, was also adapted for the small and large intestine. In this review the application of precision-cut intestinal slices (PCIS) for research in drug metabolism and transport is discussed.

PCIS can be prepared from animal and human tissue from all regions of the intestine allowing investigating species differences and regional gradients of activities of metabolizing enzymes. They are viable for 8-24 h of incubation and show high activity of drug metabolizing enzymes, representative for the in vivo activity. They have been successfully used to study drug-drug interactions such as induction, inhibition and regulation of drug metabolizing enzymes, transporters and nuclear factors. Moreover they appear to be a suitable model for studies on cold preservation of donor organs for transplantation, and allow exploring inter-organ interactions by co-incubation with precision-cut slices of other organs. Their application as model for drug-induced intestinal toxicity is still in its infancy but appears to be promising. PCIS, prepared from human and animal tissue, represent a powerful translational model for drug metabolism, transport and toxicity studies and as such contributes to the reduction and replacement of animal experiments.
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In vitro methods to study the interplay of drug metabolism and efflux in the intestine
Sanna Siissalo and Aki T. Heikkinen
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00270]

This review provides an overview of the in vitro methods currently used in studies of intestinal drug metabolism and active efflux with a special emphasis on the efflux- metabolism interplay. These methods include e.g. expressed enzymes or efflux transporters, fractionated intestinal cells, cell lines, primary cells, intestinal segments and other tissue preparations. Pharmacokinetics of efflux-metabolism interplay is often very complicated, possibly involving saturation, stimulation and/or inhibition of one or both of these mechanisms. Parent drug and/or metabolite(s) can be substrates for several enzymes and/or efflux proteins. These detoxifying proteins may alter the exposure of drugs to each other and, consequently, their contributions to the overall drug elimination. Depending on the complexity of the in vitro system used, different kinds of information can be extracted from the results. Simple methods concentrating on single mechanisms provide easily interpretable information, but neglect the interplay between various mechanisms influencing the kinetics in a whole organism. More complex experimental systems mimic the mechanistic complexity of in vivo setting better, but at the same time the interpretation and utilization of the results becomes more challenging.

Advantages and limitations of various in vitro systems are addressed and consideration given to the physiological relevance of the results obtained and discussion of approaches for in vitro - in vivo translation of the data.
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Do the Recommended Standards for In Vitro Biopharmaceutic Classification of Drug Permeability Meet the "Passive Transport" Criterion for Biowaivers?
Žakelj Simon, Berginc Katja, Roškar Robert, Kraljič Bor and Kristl Albin
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00271]

BCS based biowaivers are recognized by major regulatory agencies. An application for a biowaiver can be supported by or even based on "in vitro" measurements of drug permeability. However, guidelines limit the application of biowaivers to drug substances that are transported only by passive mechanisms. Regarding published permeability data as well as measurements obtained in our institution, one can rarely observe drug substances that conform to this very strict criterion.

Therefore, we measured the apparent permeability coefficients of 13 drugs recommended by FDA's Guidance to be used as standards for "in vitro" permeability classification. The asymmetry of permeability data determined for both directions (mucosal-to-serosal and serosal-to-mucosal) through the rat small intestine revealed significant active transport for four out of the nine high-permeability standards and for all four low-permeability standard drugs. As could be expected, this asymmetry was abolished at 4°C on rat intestine. The permeability of all nine high-permeability, but none of the low permeability standards, was also much lower when measured with intestinal tissue, Caco-2 cell monolayers or artificial membranes at 4°C compared to standard conditions (37°C). Additionally, concurrent testing of several standard drugs revealed that membrane transport can be affected by the use of internal permeability standards.

The implications of the results are discussed regarding the regulatory aspects of biopharmaceutical classification, good practice in drug permeability evaluation and regarding the general relevance of transport proteins with broad specificity in drug absorption.
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Aspirin as a chemoprevention agent for Colorectal cancer
Chun Seng Lee, Deirdre McNamara and Colm Antoine O’Morain
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00272]

Colorectal cancer (CRC) is one of the leading causes of mortality in the western world. It is widely accepted that neoplasms such as colonic polyps are precursors to CRC formation; with the polyp-adenoma-carcinoma sequences well described in medical literature [1, 2] It has been shown that Aspirin and other non-steroid anti-inflammatory drugs (NSAID) have a negative effect on polyp and cancer formation. This review aims to describe some of the mechanism behind the chemoprotective properties of aspirin; COX 2 inhibition, regulation of proliferation and apoptosis and effects on the immune system and also the current evidence that supports its use as a chemoprevention agent against CRC. We will also aim to explore the side effects with the use of aspirin and the pitfalls of using aspirin routinely for primary prophylaxis against CRC.
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Is the autophagy induced by thiopurines beneficial or deleterious?
Luis G. Guijarro, Irene D. Román, M. Dolores Fernández-Moreno,  Javier P. Gisbert and Borja Hernández-Breijo
[Purchase Article] [BSP/CDM/E-Pub/00273]

Thiopurines (azathioprine, 6-mercaptopurine and 6-thioguanine), are drugs useful in the treatment of leukemia, autoimmune diseases, as well as in organ transplantation. After many years of use is still not well understood their mode of action. Recently, several groups have found that thiopurines can activate autophagy by different mechanisms. Autophagy is a process of auto-digestion. After an infection, radiation, injury, oxidative stress, or after drug treatment, the cellular organelles may be damaged. In those cases the damaged structures are recognized by the cell, isolated in a double-membrane vacuole and finally degraded in autolysosomes. The digestion gives rise to biosynthetic precursors needed to regenerate partially destroyed structures, so as to produce the energy essential in the anabolic process. During fasting, the protein aggregates, lipid droplets and glycogen deposits are degraded by this pathway for releasing nutrients to the blood. Therefore this process is of vital importance in the maintaining of cellular functions and in the systemic homeostasis of whole organism. The therapy with thiopurines leads to adverse effects such as myelosuppression and hepatotoxicity whose mechanism is not well understood today. Autophagy is also involved in liver degeneration induced by drugs, alcohol or viruses. Therefore, seems to be very attractive know whether the autophagy induced by thiopurines is the cause of the hepatotoxicity associated with these drugs, or rather, autophagy is a compensatory  response that protects the liver against the deleterious effects of the thiopurines. Our results and previous data suggest that autophagy is beneficial for the liver because protects it against the deleterious effects of thiopurines.
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The influence of CYP2C19 genetic polymorphism on the pharmacokinetics/pharmacodynamics of proton pump inhibitor-containing Helicobacter pylori treatments
D.R. Serrano, S. Torrado, S. Torrado-Santiago and J.P. Gisbert
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00274]

Proton pump inhibitors (PPIs) are the most potent acid suppressants available. PPIs undergo hepatic metabolism via the CYP2C system for the isoforms CYP2C19 and CYP3A4 in particular. Genetic polymorphisms in CYP2C19 may affect the metabolism of individual PPIs to different extents. Although PPIs are highly effective as a class, differences in their pharmacokinetics, such as bioavailability and metabolism, may translate into differences in clinical outcomes. In Helicobacter pylori infection, a significantly lower eradication rate was seen in extensive metabolisers with omeprazole but no with rabeprazole.
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Drug Treatment of Eosinophilic Oesophagitis
S. O'Donnell, OB. Kelly and C. O'Morain
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00275]

Eosinophilic oesophagitis is a clinicopathological disease characterised by oesophageal eosinophilia and gastrointestinal symptoms.  Currently, the optimal treatment regimens remain unclear.  The pathogenesis of eosinophilic oesophagitis appears to involve immune dysregulation, while acid reflux may have a secondary role; the mainstays in treatment are aimed principally at these dual processes.  While a trial of a PPI is worthwhile it is likely that PPI therapy is treating concurrent acid reflux rather than true eosinophilic oesophagitis.  Dietary elimination with elemental feed is safe but poorly tolerated.  Swallowed topical steroids are the mainstay of commercially available therapies.  Both fluticasone and budesonide have been proven to be beneficial both symptomatically and in reducing oesophageal eosinophil counts in the short and medium term.  Basic studies have determined a role for IL-5 in oesophageal remodelling in eosinophilic esophagitis. Initial clinical studies have shown single or multiple infusions of monoclonal antibody to IL-5 to be well tolerated and to cause a long-term decrease in both peripheral and sputum eosinophil count in these eosinophil driven conditions.    At present, swallowed corticosteroids are the mainstay of treatment for patients with eosinophilic oesophagitis in patients failing PPI therapy.  Studies have been heterogenous in their diagnostic criteria for eosinophilic oesophagitis and in the definition of response to therapy, making comparison of results difficult.
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Utility of assessing thiopurine S-methyltransferase polymorphisms before azathioprine therapy
Teresa Cabaleiro, Manuel Román, Javier P. Gisbert and Francisco Abad-Santos
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00276]

Thiopurine S-methyltransferase (TPMT) catalyzes the methylation of thiopurine drugs, such as azathioprine and mercaptopurine, which are used in a variety of diseases. Several mutations in the TPMT gene correlate with low enzyme activity and subsequent adverse effects, mainly myelotoxicity. Hence, genotyping TPMT makes it possible to identify patients at high risk of drug toxicity and adjust dosage accordingly. However, further research about the availability of a reliable and universal screening method and more cost-effectiveness studies are necessary.
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Vitamin D: New Roles and Therapeutic Potential in Inflammatory Bowel Disease
Tara Raftery, Colm O’Morain and Maria O’Sullivan
[Purchase Article] [BSP/CDM/E-Pub/00277]

Inflammatory bowel disease (IBD) encompasses 2 independent but related entities: ulcerative colitis (UC) and Crohn’s disease. Crohn’s disease is characterised by transmural patchy inflammation which can involve any portion of the gastrointestinal tract. UC is characterized by superficial inflammation that begins in the rectum and extends proximally along the colon. In Europe approximately 2.2 million people have a diagnosis of IBD. The aetiology of IBD is unknown however immune, environmental and genetic factors are thought to be involved.

Individuals with IBD are at risk of developing osteoporosis. In line with this, there are clear guidelines that recommend vitamin D supplementation for IBD patients to prevent bone disease, especially when undergoing steroid treatment. Despite an established role for vitamin D in IBD, deficiency is common. More novel effects of vitamin D beyond bone are emerging. It is now well established that vitamin D is an important regulator of the immune system which may have implications for the development, severity and management of immune related disorders such as IBD. The efficacy of vitamin D as an immune modulator in IBD remains to be proven. This review aims to evaluate the evidence implicating vitamin D deficiency in IBD pathogenesis, to examine vitamin D’s anti-inflammatory mechanisms and to explore its therapeutic potential, optimal serum levels and dietary intakes which may support immune function in this disease.
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Strategies For Improving The Quantitative Bioanalytical Performance Of Lc–Ms In Pharmacokinetic Studies
Li Li, Dandan Tian, Junling Yang, Feng Chen, Ke Yu and Yan Sun
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00278]

Quantitative bioanalysis is urgently required for evaluation the pharmacokinetic properties of a drug and demonstrate the body exposure to the parent drug and/or metabolite for interpretation of the efficiency and toxicity. New trends in drug discovery and development will be always posing challenges on LC–MS-based quantitative bioanalysis. The focus of this minireview is to highlight the commonly used strategies for improving the quantitative bioanalytical performance including overcoming matrix effects and improving MS detectability. “LC-electrolyte effects” and “pulse gradient chromatography” proposed by our group are new approaches that have also showed potential efficiencies on improving overall bioassay performance, including lowering lower limit of quantification, enlarging upper limit of quantification, decreasing matrix effects, and overcoming elutropic effects, etc. They should also work well in metabolic profiling studies and other important analytical fields, such as food pesticide residue analysis, environmental analysis, clinical and forensic toxicology, doping control, and so on.
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Isotopic labeling of metabolites in drug discovery applications
Jacobo Iglesias, Lekha Sleno and Dietrich A. Volmer
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00279]

Understanding the metabolic and pharmacokinetic fate of a drug in humans is a key factor in its development and registration, as well as in the elaboration of new therapeutic agents. To carry out these studies, stable isotope labeling techniques have been effectively used by drug metabolism scientists and toxicologists in order to gain better understanding of drugs’ disposition, bioavailability and toxicity in in vivo studies. Among the different analytical techniques used, mass spectrometry (MS) coupled to separation techniques has become the detection method of choice due to its high sensitivity and selectivity. In vitro quantification of metabolite levels in biofluids by MS is often difficult if a proper internal standard is not available due to the inherent problems associated with the technique (e.g. chromatographic coelutions, ion suppression, low reproducibility etc.). Stable isotope coding approaches alleviate these drawbacks and allow comparative drug metabolomics studies similarly to the differential proteomic techniques developed in the last decade. This review describes a selection of methodological improvements in the use of stable isotopes labeling in combination with MS to detect drug metabolites. In the first part of the paper, the application of labeled compounds to study the absorption, distribution, metabolism, excretion and toxicology of drugs (ADMET) in addition to the elucidation of metabolic pathways is presented. In the second part, recent developments of stable isotope coded tags for the in vitro relative metabolite quantification in biofluids are presented.
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Liquid Chromatography-Mass Spectrometric Multiple Reaction Monitoring-based Strategies for Expanding Targeted Profiling towards Quantitative Metabolomics
Bin Guo, Bo Chen, Aiming Liu, Weitao Zhu and Shouzhuo Yao
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00280]

Recent advances in analytical methodologies have made it possible to bring the metabolomic profiling into the field of quantitative metabolomics that permits precise measurements of comprehensive small-molecule profiles within a biological system. Modern liquid chromatography-tandem mass spectrometry (LC-MS/MS) with multiple reaction monitoring (MRM) mode serves as the foundation for accurate simultaneous multi-analyte quantitation across large sample sets to provide high-quality and valuable information on target molecular profiles in complex systems. Despite the intrinsic multiplexing potential of the LC-MRM-MS technique, the key bottleneck in current LC-MRM-based assays is generally the limited analyte coverage and throughput capacity. Nowadays, the MRM-based approach has emerged as an attractive strategy for quantitative proteomic analysis and high-throughput biomarker discovery. So far, the full potential of the contemporary LC-MRM methodology unleashed for quantitative metabolite profiling and metabolomic measurements of non-petidic small molecules is rarely discussed. In this review we attempt to provide an overview on the major recent developments in LC-MRM-based strategies for quantitative profiling of multi- and non-target small molecules in biological samples. This article highlights the utility and power of the LC-MRM-based targeted approaches as valuable bioanalytical tools for low-cost, multiplexed quantitation on a large scale, with special emphasis on the promise of combining various strategies for expanding coverage and throughput of the LC-MRM-based assays with multivariate statistical methods to cover the gap between a widely targeted profiling and the conventional large-scale unknown screening towards comparative or quantitative metabolomics. General issues raised in metabolite profiling, such as current aspects of bioanalysis, methodological dilemmas and basic challenges in quantitative metabolomics are addressed, and different strategies to circumvent the existing bottleneck and potential pitfalls of the conventional LC-MRM-MS techniques are outlined and proposed. In addition, a brief description of the rudiments of LC-MRM-MS and its recent applications in combination with such strategies for biomarker quantitation and verification is also described.
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LC/MS Based Tools and Strategies on Qualitative and Quantitative Analysis of Herbal Components in Complex Matrixes
Liang Wu, Haiping Hao and Guangji Wang
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00281]

Accompanying with hot discussions on developing multi-target drugs for the therapy of multi-gene diseases, herbal medicines are receiving more and more attention worldwide in both academic and industrial fields. Pharmacokinetic and metabolic research is one of the important issues for intensive understanding of therapeutic benefits/risks of herbal medicines. The qualitative and quantitative analysis of herbal medicines, which is a prerequisite for pharmacokinetic and metabolic evaluations, remains a great challenge because of the intrinsic complexity of herbal medicines. This paper provides a review on the recent development of qualitative and quantitative methodologies on herbal medicines analysis. Powerful hybrid mass spectrometric tools such as Q-TOF and IT-TOF are highly useful for both the qualitative and quantitative analysis of complicated components. In the past decade, some universal useful strategies to the qualitative and quantitative analysis and pharmacokinetic assessment of complicated herbal components have been also proposed. Nonetheless, it is urgent to develop additional strategies to resolve the critical challenges underlying herbal analyses, such as the lack of authentic compounds, the difficulties in information processing, and the elimination of complex matrixes interferences.
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Lc-Ms Based Screening And Targeted Profiling Methods For Complex Plant: Coffee A Case Study
Jeane Santos da Rosa, Otniel Freitas-Silva, Sidney Pacheco, Ronoel Luiz de Oliveira Godoy and Claudia Maria Moraes Rezende
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00282]

In the recent years the way of thinking about human health necessarily passes by human food. Recent discoveries do not only concern about valuable biomolecules but also contaminants. Thus, the screening of substances in animal and vegetable matrices by analytical techniques is focused on the presence and absence of target substance. In both cases, the majority of these substances are present as traces or in very low levels. Contaminants could be naturally present in the food, inserted on it or even developed on it as a consequence of food processing or cooking. Pesticides, mycotoxins, dioxins, acrylamide, Sudan red, melamine and now 4(5)-methylimidazole can be, at present, be listed as some of the world big problems related to food contaminants and adulterants. With the development of liquid chromatography coupled to mass spectrometry (LC-MS-MS), in the last few decades, analysis of some food contaminants in trace levels trace become less laborious, more accurate and precise. The multiple approach of those techniques make possible to obtain many results in one single run. On the other hand, European Union (2002/657/EC) established regulations for analytical methods regarding mass spectrometry as detection tool, showing the importance of this technique in food quality control. The EU criteria uses identification points (IPs) that could be achieved basically with four product ions (including molecular ion) or reduced with the use of high resolution equipments. This kind of mass spectrometers made the IPs criteria more accessible, as the exact mass information is a differential tool. In view of this the aim of this review is to present the actual scenario for mass spectrometry analysis in a complex vegetable food matrix such as roasted coffee, with emphasis on needs and challenges regarding the LC-MS technique in order to meet and contribute to food safety standards in this complex matrix.
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Importance of Metabolic Activation Study to the Safe Use of Chinese Herbal Medicines
Bin Ma, Na Li and Ge Lin
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00283]

The number of new drugs approved for clinical use per year is falling in the last decade. One approach to reduce the high rate of attrition during early drug development is to systematically determine the toxic metabolites on the mechanism basis. Traditional Chinese herbal medicines (CHM) have been used extensively for disease treatment and health care. Recently, they have also been used as raw materials for preparation of herbal dietary supplements and nutraceuticals worldwide. However, problems arise due to the adverse effects caused by CHM and their derived products. Similar to synthetic drugs, among the diverse mechanisms the metabolism-induced adverse effect/toxicity is an important safety issue of CHM. For safe use of CHM and herbal products, it is also necessary to study herbinduced toxicities using the mechanism-based approach. CHM consist of multi-ingredients, which makes the study of toxic metabolites more difficult and challenging than that of synthetic drug-induced toxicity. In this mini-review, using hepatotoxicity and nephrotoxicity induced respectively by metabolic activation of pyrrolizidine alkaloids and aristolochic acid present in CHM as examples, we address the significance of metabolic study of CHM and how it contributes to the delineation of the toxic mechanisms, development of mechanismbased biomarkers for the diagnosis and assessment of adverse effect/toxicity of CHM, prediction of toxic dosage, and reduction and prevention of toxicity of CHM.
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Metabolic Conversion from Co-existing Ingredient Leading to Significant Systemic
Exposure of Z-butylidenephthalide, a Minor Ingredient in Chuanxiong Rhizoma in
Rat
Ru Yan, Nga Ling Ko, Bin Ma, Yun Kau Tam and Ge Lin
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00284]

Pharmacokinetic (PK) study of medicinal herbs is a great challenge, because which component(s) is(are) the bioactive ingredients is largely unknown. Most of the reported PK studies of herbs focused on the major ingredients regardless of their in vivo bioactivities, while PK of components with low content in herbs is often ignored. The present study demonstrates how PK study can reveal potential importance of a low content ingredient to the herbal bioactivities using Z-butylidenephthalide (BuPh), a bioactive phthalide present in a significantly low quantity in medicinal herb Chuanxiong Rhizoma, as an example. PK of BuPh was investigated in rats using Chuanxiong extract, fraction containing BuPh and ligustilide, and pure BuPh, respectively. The results demonstrated that remarkable blood concentrations of BuPh were observed after administration of the herbal extract and its systemic exposure was significantly different between BuPh given in pure and mixed forms. More interestingly, AUC of BuPh via intake of fraction (9.3-fold) and extract (4.5-fold) was significantly greater than that obtained from pure BuPh, which was further evidenced to be mainly due to metabolic conversion from ligustilide, a major component in Chuanxiong. Our findings revealed that although it naturally occurred in low amount, BuPh reached significant systemic concentrations via metabolic conversion from ligustilide. Moreover, our results demonstrated that PK study is one of crucial and inevitable steps for revealing in vivo bioactive ingredients of herbal medicines, and such studies should be more appropriate to focus on in vivo profile of the ingredients co-existing in herbs rather than only studying them individually.
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Measurement of CYP1A2 Activity: A Focus on Caffeine as a Probe
Vidya Perera, Annette S. Gross and Andrew J. McLachlan
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00285]

The drug metabolising enzyme CYP1A2 contributes to the metabolism of a number of medicines including clozapine, olanzapine and theophylline. These medicines display a high degree of inter-individual variability in pharmacokinetics and response. Measuring CYP1A2 activity in vivo can be an important tool to identify the factors that influence variability in drug pharmacokinetics and inform dose selection. Caffeine is the only currently accepted probe to conduct in vivo phenotyping of CYP1A2. Despite the number of proposed matrices (biological fluid containing the drug and/or metabolite/s of interest) and metrics (mathematical formula relating the drug and/or metabolite/s to enzyme activity) proposed to measure CYP1A2 activity using caffeine, many of these are compromised by factors related to the specific metabolic pathway studied or pharmacokinetic characteristics of caffeine and its metabolites. Furthermore, questions regarding the appropriate study design and methodology to conduct studies to evaluate CYP1A2 activity have often been overlooked. These issues include the potential influence of a methylxanthine abstinence period prior to caffeine CYP1A2 phenotyping and the impact of caffeine formulation on determining CYP1A2.
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Uptake and metabolism of the short-chain fatty acid butyrate, a critical review of the literature
Stuart M. Astbury and Bernard M. Corfe
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00286]

Butyrate is a short-chain fatty acid (SCFA) formed by bacterial fermentation of fibre in the colon, and serves as anenergy source for colonocytes. The action of butyrate as a histone deacetylase inhibitor (HDACi) has led to a number of clinical trials testing its effectiveness as a potential treatment for cancer. The biology of butyrate transport is therefore relevant to both its physiological and pharmacological benefits. This review of the literature was carried out to assess the evidence for both the uptake and metabolism of butyrate, in an attempt to determine possible mechanism(s) by which butyrate can act as an HDACi. It is noted that although uptake and metabolism are well characterised, there are still significant gaps in the knowledgebase around the intracellular handing of butyrate, where assumptions or dated evidence are relied upon.
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Active Metabolites Resulting from Decarboxylation, Reduction and Ester Hydrolysis of Parent Drugs
I. Hartyánszky, H, Kalász , E. Adeghate , Zs. Gulyás, M.Y. Hasan, K. Tekes, A. Adem and P. Sótonyi
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00287]

Decarboxylation, reduction and hydrolysis can yield active metabolites from the parent drug. Major therapeutic indications and metabolic routes of these drugs are reviewed. Changes in the logP values (determined and calculated) from the parent drug to the active metabolite show certain characteristics in comparison to other phase I metabolic alterations. Metabolic decarboxylation of parent drug is commonly associated with increase in lipophilicity. However, in some cases, decarboxylation may cause a reduction in lipophilicity. Ester hydrolysis generally unmasks either the polar carboxylic or hydroxyl group with the outcome of an increase in hydrophilicity. On the contrary, hydrolysis of phosphate ester means a huge increase in the lipophilic character of the drug, as the highly polar phosphate group is removed.
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Summary of Information on the Effects of Ionizing and Non-ionizing Radiation on Cytochrome P450 and Other Drug Metabolizing Enzymes and Transporters
Slobodan Rendic and F. Peter Guengerich
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00288]

The present paper is an update of data on the effects of ionizing radiation (γ-rays, X-rays, high energy UV, fast neutron) caused by environmental pollution or clinical treatments and the effects of non-ionizing radiation (low energy UV) on the expression and/or activity of drug metabolism (e.g., cytochrome P450 (CYP), glutathione transferase (GST)), enzymes involved in oxidative stress (e.g., peroxidases, catalase (CAT), aconitase (ACO), superoxide dismutase (SOD)), and transporters. The data are presented in tabular form (Tables 1-3) and are a continuation of previously published summaries on the effects of drugs and other chemicals on cytochrome P450 enzymes (Rendic, S.; Di Carlo, F. Drug Metab. Rev., 1997, 29 (1-2), 413-580, Rendic, S. Drug Metab. Rev., 2002, 34 (1-2), 83- 448) and of the data on the effects of diseases and environmental factors on the expression and/or activity of human cytochrome P450 enzymes and transporters (Guengerich, F.P.; Rendic, S. Curr. Drug Metab., 2010, 11(1), 1-3, Rendic, S.; Guengerich, F.P. Curr. Drug Metab., 2010, 11 (1), 4-84). The collective information is as presented by the cited author(s) in cases where several references are cited the latest published information is included. Remarks and conclusions suggesting clinically important impacts are highlighted, followed by discussion of the major findings. The searchable database is available as an Excel file (for information about file availability contact the corresponding author).
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Physiologically Based Pharmacokinetic Models: Integration of In Silico Approaches with Micro Cell Culture Analogues
T. Maguire, A. Chen and M.L.Yarmush
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00289]

There is a large emphasis within the pharmaceutical industry to provide tools that will allow early research and development groups to better predict dose ranges for and metabolic responses of candidate molecules in a high throughput manner, prior to entering clinical trials. These tools incorporate approaches ranging from PBPK, QSAR, and molecular dynamics simulations in the in silico realm, to micro cell culture analogue (CCAs)s in the in vitro realm. This paper will serve to review these areas of high throughput predictive research, and highlight hurdles and potential solutions. In particular we will focus on CCAs, as their incorporation with PBPK modeling has the potential to replace animal testing, with a more predictive assay that can combine multiple organ analogs on one microfluidic platform in physiologically correct volume ratios. While several advantages arise from the current embodiments of CCAS in a microfluidic format that can be exploited for realistic simulations of drug absorption, metabolism and action, we explore some of the concerns with these systems, and provide a potential path forward to realizing animal-free solutions. Furthermore we envision that, together with theoretical modeling, CCAs may produce reliable predictions of the efficacy of newly developed drugs.
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Intracellular Disposition of Methotrexate in Acute Lymphoblastic Leukemia in Children
Tiphaine Adam de Beaumais and Evelyne Jacqz-Aigrain
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00290]

Methotrexate (MTX) is a key agent for the treatment of acute lymphoblastic leukemia in children and the benefit of high-dose MTX is well established as it significantly increases cure rates and improves patients’ prognosis. However, the determinants of MTX therapeutic effect are not clearly identified, although intracellular polyglutamation is essential. MTX, the monoglutamate form (MTXG1) inhibits the dihydrofolate reductase (DHFR) implicated in the folate cycle. MTXG1 is metabolized to active methotrexate polyglutamates (MTXPG) with sequential gamma-linkage of 2 to 6 glutamyl residues by the folylpolyglutamate synthetase (FPGS). Long chain MTXPG have higher affinity than MTX for the enzymes involved in de novo purine synthesis such as 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC) and thymidilate synthase (TS), which results in a reinforcement of MTX inhibition. Thus, intracellular formation of MTXPG enhances the cytotoxic and antileukemic effect of MTX. Different pharmacogenetic polymorphisms contribute to interindividual variability in MTX response to treatment. In addition, pharmacokinetic interactions with 6-mercaptopurine (6-MP), frequently co-administered, have been reported And factors affecting intracellular MTX disposition and 6-MP/MTX interactions, including pharmacogenetic polymorphisms affecting MTX disposition are reviewed.
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Comparison of Cytochrome P450 2C Subfamily Members in Terms of Drug Oxidation Rates and Substrate Inhibition
Toshiro Niwa and Hiroshi Yamazaki
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00291]

This review focuses on identification of important active-site residues of the cytochrome P450 2C (CYP2C) subfamily in terms of substrate specificity. A meta-analysis was performed on the reported literature regarding (1) values of the Michaelis-Menten constant (Km), maximal velocity (Vmax), and intrinsic clearance (Vmax/Km) for 74 metabolic reactions of 45 substrates mediated by human CYP2C8, CYP2C9, CYP2C18, and CYP2C19 and (2) inhibition constants (Ki) for 3 inhibitors. Although the kinetic behaviors of these CYP2C subfamily members depend on the metabolic reaction, the ratios of Vmax/Km values for CYP2C19/CYP2C9 and CYP2C8/CYP2C19, but not for CYP2C8/CYP2C9, were more closely correlated with Km values than with Vmax values, suggesting that, for many metabolic reactions, differences in affinity may be more important than differences in capacity for the substrate/reaction specificity of the CYP2C subfamily, especially for CYP2C19. In addition, it has been proposed that the residues involved in substrate recognition sites (SRS) 1, SRS 3, and/or SRS 4 are important for the metabolizing capacity and/or the substrate binding of CYP2C9 and CYP2C19. In contrast to the reasonable amount of kinetic data available, there are few reports comparing the effects of inhibitors [inhibitory constant (Ki) or 50% inhibitory concentration (IC50)] on metabolic reactions mediated by the CYP2C subfamily. Collectively, these findings provide insights into the contributions of CYP2C subfamily members to drug metabolism and adverse drug interactions.
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Implications of Nanoscale Based Drug Delivery Systems in Delivery and Targeting Tubulin Binding Agent, Noscapine in Cancer Cells
Ramesh Chandra, Jitender Madan, Prashant Singh, Ankush Chandra, Pradeep Kumar, Vritika Tomar and Sujata K. Dass
[FULL-TEXT INQUIRY] [BSP/CDM/E-Pub/00292]

Noscapine, a tubulin binding anticancer agent undergoing Phase I/II clinical trials, inhibits tumor growth in nude mice bearing human xenografts of breast, lung, ovarian, brain, and prostrate origin. The analogues of noscapine like 9-bromonoscapine (EM011) is 5 to 10-fold more active than parent compound, noscapine. Noscapinoids inhibit the proliferation of cancer cells that are resistant to paclitaxel and epothilone. Noscapine also potentiated the anticancer activity of doxorubicin in a synergistic manner against triple negative breast cancer (TNBC). However, physicochemical and pharmacokinetic (ED50~300-600 mg/kg bodyweight) limitations of noscapine present hurdle in development of commercial anticancer formulations. Therefore, objectives of the present review are to summarize the chemotherapeutic potential of noscapine and implications of nanoscale based drug delivery systems in enhancing the therapeutic efficacy of noscapine in cancer cells. We have constructed noscapine-enveloped gelatin nanoparticles, NPs and poly (ethylene glycol) grafted gelatin NPs as well as inclusion complex of noscapine in β-cyclodextrin (β-CD) and evaluated their physicochemical characteristics. The Fe3O4 NPs were also used to prepare noscapine loaded magnetic polymeric NPs (NMNP) which encapsulate the noscapine on the surface of the polymer matrix, whereas the molecular weight of polymer plays a crucial role in the capacity of drug loading on the polymer surface. The enhanced noscapine delivery using βPAR-targeted optical-MR imaging trackable NPs offer a great potential for image directed targeted delivery of noscapine. Human Serum Albumin NPs (150-300 nm) as efficient noscapine drug delivery systems have also been developed for potential use in breast cancer.
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