ISSN: 1389-2002

OPEN ACCESS PLUS


Contents


Impact of Genetic Polymorphisms and Drug–Drug Interactions on Clopidogrel and Prasugrel Response Variability, 2010, 11, 667-677
V. Ancrenaz, Y. Daali, P. Fontana, M. Besson, C. Samer, P. Dayer and J. Desmeules
[Abstract] [Full Text Article]


Systematic Evaluation of Dose Proportionality Studies in Clinical Pharmacokinetics, 2010, 11, 526-537
Yucheng Sheng, Yingchun He, Xiaohui Huang, Juan Yang, Kun Wang and Qingshan Zheng
[Abstract] [Full Text Article]


Atypical Antipsychotic Metabolism and Excretion, 2010, 11, 516-525
J.J. Sheehan, J.K. Sliwa, J.C. Amatniek, A. Grinspan and C.M. Canuso
[Abstract] [Full Text Article]


Bioavailability of Flavonoids: A Review of Their Membrane Transport and the Function of Bilitranslocase in Animal and Plant Organisms, 2009, 10, 369-394
Sabina Passamonti, Michela Terdoslavich, Raffaella Franca, Andreja Vanzo, Federica Tramer, Enrico Braidot, Elisa Petrussa and Angelo Vianello
[Abstract] [Full Text Article]


Biological Actions and Metabolism of Currently Used Pharmacological Agents for the Treatment of Congestive Heart Failure, 2009, 10, 206-219
H.K. Saini-Chohan and G.M. Hatch
[Abstract] [Full Text Article]


Arylamine N-Acetyltransferases in Mycobacteria, 2008, 9, 510-519
E. Sim, J. Sandy, D. Evangelopoulos, E. Fullam, S. Bhakta, I. Westwood, A. Krylova, N. Lack and M. Noble
[Abstract] [Full Text Article]


Lack of Interaction of the NMDA Receptor Antagonists Dextromethorphan and Dextrorphan with P-Glycoprotein, 2008, 9, 144-151
M. Kanaan, Y. Daali, P. Dayer and J. Desmeules
[Abstract] [Full Text Article]


Xenobiotic-Induced Transcriptional Regulation of Xenobiotic Metabolizing Enzymes of the Cytochrome P450 Superfamily in Human Extrahepatic Tissues, 2008, 9, 129-143
P. Pavek and Z. Dvorak
[Abstract] [Full Text Article]


Early Development of Therapeutic Biologics – Pharmacokinetics, 2006, 7, 15-21
A. Baumann
[Abstract] [Full Text Article]




Abstracts


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Impact of Genetic Polymorphisms and Drug–Drug Interactions on Clopidogrel and Prasugrel Response Variability
V. Ancrenaz, Y. Daali, P. Fontana, M. Besson, C. Samer, P. Dayer and J. Desmeules

[Full Text Article]

Thienopyridine antiaggregating platelet agents (clopidogrel and prasugrel) act as irreversible P2Y12 receptor inhibitors. They are used with aspirin to prevent thrombotic complications after an acute coronary syndrome or percutaneous coronary intervention. A large interindividual variability in response to clopidogrel and to a lesser extent to prasugrel is observed and may be related to their metabolism. Clopidogrel and prasugrel are indeed prodrugs converted into their respective active metabolites by several cytochromes P450 (CYPs). Besides clopidogrel inactivation (85%) by esterases to the carboxylic acid, clopidogrel is metabolized by CYPs to 2-oxoclopidogrel (15%) and further metabolized to an unstable but potent platelet-aggregating inhibitor. Prasugrel is more potent than clopidogrel with a better bioavailability and lower pharmacodynamic variability. Prasugrel is completely converted by esterases to an intermediate oxo-metabolite (R-95913) further bioactivated by CYPs. Numerous clinical studies have shown the influence of CYP2C19 polymorphism on clopidogrel antiplatelet activity. Moreover, unwanted drug–drug pharmacokinetic interactions influencing CYP2C19 activity and clopidogrel bioactivation such as with proton pump inhibitors remain a matter of intense controversy. Several studies have also demonstrated that CYP3A4/5 and CYP1A2 are important in clopidogrel bioactivation and should also be considered as potential targets for unwanted drug–drug interactions. Prasugrel bioactivation is mainly related to CYP3A4 and 2B6 activity and therefore the question of the effect of drug–drug interaction on its activity is open. The purpose of this review is to critically examine the current literature evaluating the influence of genetic and environmental factors such as unwanted drug–drug interaction affecting clopidogrel and prasugrel antiplatelet activity.


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Systematic Evaluation of Dose Proportionality Studies in Clinical Pharmacokinetics
Yucheng Sheng, Yingchun He, Xiaohui Huang, Juan Yang, Kun Wang and Qingshan Zheng

[Full Text Article]

An understanding of dose proportionality is essential in drug development, and the results are of great clinical importance for predicting the effects of dose adjustments. However, little consensus exists with regard to study design and analysis. The aim of this paper was to produce a detailed profile of the information on dose proportionality studies in the last 10 years and to provide a foundation for reflection and debate on future priorities. A total of 147 publications comprising 156 studies were analyzed. The typical dose proportionality study enrolled 20 to 30 subjects and randomly allocated them into 3 to 4 dose levels to investigate pharmacokinetic behaviors within a dose ratio range of 2-6. The most common design was the crossover experiment (52.6%), and evaluating dose-adjusted pharmacokinetic parameters followed by hypothesis testing (43%) was the most frequent statistical approach. However, the alternative crossover design and equivalence criterion based on the power model represented only 4% and 8% of studies, respectively. The power model as a recommendable empirical relationship to assess dose proportionality was applied in 25 (16%) studies. This research suggests that the al-ternative crossover design and power model statistical method should be attracting more attention in order to obtain more information in studies with limited subjects.


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Atypical Antipsychotic Metabolism and Excretion
J.J. Sheehan, J.K. Sliwa, J.C. Amatniek, A. Grinspan and C.M. Canuso

[Full Text Article]

Background: The metabolic/biotransformation pathways of atypical antipsychotics (aripiprazole, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone) have been characterized and reviewed. However, comparisons of excretory pathways remain unexplored. Objective: To analyze the excretion profile of atypical antipsychotic agents and compare the overall magni-tude of metabolism (changed vs. unchanged drug) and route of excretion (feces vs. urine). Secondary objectives include providing: 1) dosing information in hepatic and renal impairment, and 2) context of the specific enzymes and pathways involved in each agent’s bio-transformation. Methods: Published literature and each manufacturer’s radiolabeled drug absorption, distribution, metabolism and excre-tion data and U.S. prescribing information were reviewed. Results: With the exception of paliperidone, atypical antipsychotics undergo extensive metabolism (i.e., ≤50% of dose recovered unchanged). Quetiapine undergoes the greatest overall metabolism (<1% of the dose recovered unchanged) and paliperidone the least (59% recovered unchanged in the urine). Between-agent differences exist in the extent of cytochrome P450 (CYP450) metabolism and the specific isozymes involved. After administration of a radioactive dose, fecal elimina-tion of unchanged drug plus metabolites ranged from 11% (paliperidone) to 71% (ziprasidone) and renal elimination ranged from 21% (ziprasidone) to 80% (paliperidone). Conclusions: Understanding the differences in the elimination profiles of atypical antipsychotics agents may permit better-informed drug and dose selection in special populations such as those with comorbid conditions (e.g. hepatitis, diabetes, end-stage renal disease) or pharmacogenetic variability; or at risk for drug-drug interactions. The use of patient tailored drug and dose-selection may result in greater treatment efficacy and a reduction in adverse events.


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Bioavailability of Flavonoids: A Review of Their Membrane Transport and the Function of Bilitranslocase in Animal and Plant Organisms
Sabina Passamonti, Michela Terdoslavich, Raffaella Franca, Andreja Vanzo, Federica Tramer, Enrico Braidot, Elisa Petrussa and Angelo Vianello

[Full Text Article]

Fruits and vegetables are rich in flavonoids, and ample epidemiological data show that diets rich in fruits and vegetables confer protection against cardiovascular, neurodegenerative and inflammatory diseases, and cancer. However, flavonoid bioavailability is reportedly very low in mammals and the molecular mechanisms of their action are still poorly known. This review focuses on membrane transport of flavonoids, a critical determinant of their bioavailability. Cellular influx and efflux transporters are reviewed for their involvement in the absorption of flavonoids from the gastro-intestinal tract and their subsequent tissue distribution. A focus on the mammalian bilirubin transporter bilitranslocase (TCDB 2.A.65.1.1) provides further insight into flavonoid bioavailability and its relationship with plasma bilirubin (an endogenous antioxidant). The general function of bilitranslocase as a flavonoid membrane transporter is further demonstrated by the occurrence of a plant homologue in organs (petals, berries) where flavonoid biosynthesis is most active. Bilitranslocase appears associated with sub-cellular membrane compartments and operates as a flavonoid membrane transporter.


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Biological Actions and Metabolism of Currently Used Pharmacological Agents for the Treatment of Congestive Heart Failure
H.K. Saini-Chohan and G.M. Hatch

[Full Text Article]

Congestive heart failure (CHF), a complex clinical syndrome with impaired cardiac pump function, occurs as a consequence of mechanical deformities (pressure and volume overload), myocardial abnormalities (neurohormonal disorders, myocarditis, cardiomyopathies, inflammation and loss of cardiomyocytes) and rhythmic defects (conduction disturbances, fibrillation and tachycardia). Several studies have demonstrated that chronic activation of sympathetic and renin-angiotensin systems, alteration in myocardial substrate utilization, increase in intracellular Ca²⁺ concentration, development of oxidative stress, release of pro-inflammatory cytokines and increased production of endothelin are responsible for the maladaptive cardiac and subcellular remodeling depending upon the type and stage of heart failure. A variety of pharmacological agents have been used to prevent the development and progression of CHF under different experimental and clinical settings. Although these drugs belong to specific classes, depending on their mechanism of action, individual drug biotransformation into different metabolites makes them distinct chemical moieties. Thorough understanding of biological effects of these pharmacological agents and metabolism is necessary to establish the basis for their preeminent use in clinical settings. The purpose of this review is to present a mechanistic understanding for the biological activities of different drugs used to treat CHF and to provide an insight of different metabolites formed after biotransformation of these chemical entities. Since development of CHF is a multifactorial and heterogeneous process, induction of combination regimens and improvement in patient compliance are the major challenges for future drug development.


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Arylamine N-Acetyltransferases in Mycobacteria
E. Sim, J. Sandy, D. Evangelopoulos, E. Fullam, S. Bhakta, I. Westwood, A. Krylova, N. Lack and M. Noble

[Full Text Article]

Polymorphic Human arylamine N-acetyl transferase (NAT2) inactivates the anti-tubercular drug isoniazid by acetyltransfer from acetylCoA. There are active NAT proteins encoded by homologous genes in mycobacteria including M. tuberculosis, M. bovis BCG, M. smegmatis and M. marinum. Crystallographic structures of NATs from M. smegmatis and M. marinum, as native enzymes and with isoniazid bound share a similar fold with the first NAT structure, Salmonella typhimurium NAT. There are three approximately equal domains and an active site essential catalytic triad of cysteine, histidine and aspartate in the first two domains. An acetyl group from acetylCoA is transferred to cysteine and then to the acetyl acceptor e.g. isoniazid. M. marinum NAT binds CoA in a more open mode compared with CoA binding to human NAT2. The structure of mycobacterial NAT may promote its role in synthesis of cell wall lipids, identified through gene deletion studies. NAT protein is essential for survival of M. bovis BCG in macrophage as are the proteins encoded by other genes in the same gene cluster (hsaA-D). HsaA-D degrade cholesterol, essential for mycobacterial survival inside macrophage. Nat expression remains to be fully understood but is co-ordinated with hsaA-D and other stress response genes in mycobacteria.

Amide synthase genes in the streptomyces are also nat homologues. The amide synthases are predicted to catalyse intramolecular amide bond formation and creation of cyclic molecules, e.g. geldanamycin. Lack of conservation of the CoA binding cleft residues of M. mari-num NAT suggests the amide synthase reaction mechanism does not involve a soluble CoA intermediate during amide formation and ring closure.


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Lack of Interaction of the NMDA Receptor Antagonists Dextromethorphan and Dextrorphan with P-Glycoprotein
M. Kanaan, Y. Daali, P. Dayer and J. Desmeules

[Full Text Article]

The anti-N-methyl-D-aspartate (NMDA) effect of dextromethorphan (DEM) seems to be mainly related to the unchanged drug rather than to its more potent metabolite dextrorphan (DOR). The aim of our study was to assess the involvement of P-glycoprotein (P-gp) and pH conditions in the transmembranal transport of these two NMDA antagonists, using a human in vitro Caco-2 cell monolayer model. Transmission electron microscopy, transepithelial electrical resistance, [³H] -mannitol permeability, Western blot analysis and the bidirectional transport of the positive controls, rhodamine and digoxine were used to confirm model’s integrity and validity. The bidirectional transport of DEM and DOR (1 to 100μM) across the monolayers was investigated in the presence and absence of the P-gp inhibitor cyclosporine A (10μM) at two pH conditions (pH 6.8/7.7-pH 7.4/7.4) and assessed with the specific and more potent P-gp inhibitor GF120918 (4μM). Analytical quantification was achieved using high performance liquid chromatography. At a pH gradient, DEM and DOR were subject to a significant active efflux transport (Papp(B-A) > 2-3x Papp(A-B); p<0.01). However, neither the influx nor the efflux was affected by P-gp inhibitors. At physiological pH, we observed no more efflux of the drugs and no influence of the inhibitors.

In conclusion, dextromethorphan and dextrorphan are not P-gp substrates. However, pH-mediated efflux mechanisms seem to be involved in limiting DEM gastrointestinal absorption. The preferential anti-NMDA central effect of DEM appears to be P-gp independent.


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Xenobiotic-Induced Transcriptional Regulation of Xenobiotic Metabolizing Enzymes of the Cytochrome P450 Superfamily in Human Extrahepatic Tissues
P. Pavek and Z. Dvorak

[Full Text Article]

Numerous members of the cytochrome P450 (CYP) superfamily are induced after exposure to a variety of xenobiotics in human liver. We have gained considerable mechanistic insights into these processes in hepatocytes and multiple ligand-activated transcription factors have been identified over the past two decades. Families CYP1, CYP2 and CYP3 involved in xenobiotic metabolism are also expressed in a range of extrahepatic tissues (e.g. intestine, brain, kidney, placenta, lung, adrenal gland, pancreas, skin, mammary gland, uterus, ovary, testes and prostate). Since the expression of the majority of the isoforms appears to be very low in the extrahepatic tissues in comparison with predominant expression in adult liver, the role of the enzymes in overall biotransformation and total body clearance is minor. However, basal expression and up-regulation of extrahepatic CYP enzymes can significantly affect local disposition of xenobiotics or endogenous compounds in peripheral tissues and thus modify their pharmacological/toxicological effects or affect absorption of xenobiotics into systemic circulation.

The goal of this review is to critically examine our current understanding of molecular mechanisms involved in induction of xenobiotic metabolizing CYP genes of human families CYP1, CYP2 and CYP3 by exogenous chemicals in extrahepatic tissues. We concentrate on organs such as the intestine, kidney, lung, placenta and skin, which are involved in drug distribution and clearance or are in direct contact with environmental xenobiotics. We also discuss single nucleotide polymorphisms (SNPs) of key CYPs, which at the level of transcription affect expression of the genes in the extrahepatic tissues or are associated with some pathophysiological stages or disorders in the organs.


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Early Development of Therapeutic Biologics – Pharmacokinetics
A. Baumann

[Full Text Article]

Modern biologics are biotechnology-derived pharmaceuticals. They are mostly used for diagnosis, prevention and treatment of serious and chronic diseases. Today, therapeutic biologics range from traditional biologics like blood and blood components, fractionated blood products, and antitoxins to modern biologics such as monoclonal antibodies, cytokines (e.g. interferon, interleukine), tissue growth factors, vaccines directed against non-infectious disease targets, and gene transfer products.

Chemical as well as pre-clinical development are major challenges for biologics due to their different physicochemical properties (mostly protein structure) compared to small molecules. They demonstrate much more complex pharmacokinetic behaviour, which strongly influences their preclinical testing strategy. Biologics are often highly species-specific in action and immunogenic in test animal species and humans. Immunogenicity of therapeutic biologics may influence their pharmacokinetic behaviour as well as pharmacodynamics and toxicity. Biologics are frequently regulated by differ-ent procedures compared to small molecules. New guidances are evolving which reflect the rapid development of new technologies in this field. Bioanalytical method development and validation is a prerequisite not exclusively for pharmacokinetic studies but for the whole pre-clinical and clinical development. Due to their unique properties, different kinds of bioanalytical assays (mass assays, activity assays, immunogenicity assays) are necessary in early development of biologics.