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Current
Drug Metabolism
ISSN: 1389-2002
Current Drug Metabolism
Volume 12, Number 4, May 2011
Contents
Hot Topic:
Analytical Aspects in Drug Metabolism
Guest Editor: Constantinos K. Zacharis
Editorial Pp. 312
Characterization of Drug Interactions with Serum
Proteins by Using High-Performance Affinity Chromatography
Pp. 313-328
D.S. Hage, J. Anguizola, O. Barnaby, A. Jackson,
M.J. Yoo, E. Papastavros, E. Pfaunmiller, M. Sobansky, and
Z. Tong
[Abstract] [Purchase
Article]
Recent Development in Liquid Chromatography/Mass
Spectrometry and Emerging Technologies for Metabolite Identification
Pp. 329-344
Y. Liang, G. Wang, L. Xie and L. Sheng
[Abstract] [Purchase
Article]
Metabolomics and its Practical Value in Pharmaceutical
Industry Pp. 345-358
R. Wei
[Abstract] [Purchase
Article]
Electrochemistry in the Mimicry of Oxidative Drug
Metabolism by Cytochrome P450s Pp. 359-371
E. Nouri-Nigjeh, R. Bischoff, A.P. Bruins and
H.P. Permentier
[Abstract] [Purchase
Article]
An Electrochemical Outlook on Tamoxifen Biotransformation:
Current and Future Prospects Pp. 372-382
J.M.P.J. Garrido, E.M.P.J. Garrido, A.M. Oliveira-Brett
and F. Borges
[Abstract] [Purchase
Article]
Conventional and Novel Approaches in Generating
and Characterization of Reactive Intermediates from Drugs/Drug
Candidates Pp. 383-394
H. Orhan and N.P.E. Vermeulen
[Abstract] [Purchase
Article]
Matrix Metalloproteinase Inhibitors: A Review
on Bioanalytical Methods, Pharmacokinetics and Metabolism
Pp. 395-410
X. Wang, K.F. Li, E. Adams and A.V.
Schepdael
[Abstract] [Purchase
Article]
Abstracts
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Characterization of Drug Interactions
with Serum Proteins by Using High-Performance Affinity Chromatography
Pp. 313-328
D.S. Hage, J. Anguizola, O. Barnaby, A. Jackson,
M.J. Yoo, E. Papastavros, E. Pfaunmiller, M. Sobansky, and
Z. Tong
The binding of drugs with serum proteins can affect the activity,
distribution, rate of excretion, and toxicity of pharmaceutical
agents in the body. One tool that can be used to quickly analyze
and characterize these interactions is high-performance affinity
chromatography (HPAC). This review shows how HPAC can be used
to study drug-protein binding and describes the various applications
of this approach when examining drug interactions with serum
proteins. Methods for determining binding constants, characterizing
binding sites, examining drug-drug interactions, and studying
drug-protein dissociation rates will be discussed. Applications
that illustrate the use of HPAC with serum binding agents
such as human serum albumin, α1-acid
glycoprotein, and lipoproteins will be presented. Recent developments
will also be examined, such as new methods for immobilizing
serum proteins in HPAC columns, the utilization of HPAC as
a tool in personalized medicine, and HPAC methods for the
high-throughput screening and characterization of drug-protein
binding.
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Recent Development in Liquid Chromatography/Mass Spectrometry
and Emerging Technologies for Metabolite Identification
Y. Liang, G. Wang, L. Xie and L. Sheng
Metabolism studies play a pivotal role in drug discovery and
development since the active metabolites is critical to toxicological
profile, efficacy and designing new drug candidates. From
the instrumentation standpoint, liquid chromatography/mass
spectrometry (LC/MS) has secured a central analytical technique
for metabolite identification with the continuous developments
and improvements in LC and MS technologies. Recently, a wide
range of experimental strategies and post acquisition data
processing and mining modes have emerged driven by the need
to identify and characterize metabolites at ever increasing
sensitivity and in ever more complex samples. In this article,
the classical and practical mass spectrometry-based techniques,
such as low resolution MS (quadruple, ion trap, linear ion
trap, etc), high resolution MS (time-of-flight, hybrid time-of-flight
instruments, Qrbitrap, Fourier transform ion cyclotron resonance
MS, etc) and corresponding post acquisition data processing
and mining modes (precursor ion filtering, neutral loss filtering,
mass defect filter, isotope-pattern-filtering, etc) are described
comprehensively. In addition, this review is also devote to
discuss several novel MS technologies (ambient ionization
techniques, ion mobility MS, imaging MS, LC/NMR/MS, etc)
that hold additional promise for the advancement of metabolism
studies.
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Metabolomics and its Practical Value in Pharmaceutical
Industry
R. Wei
Metabolomics is emerging as a promising systems biology approach
for many research fields including functional genomics, disease
diagnosis, nutrition science, and drug discovery. Following
rapid development in academic and research institutes, metabolomics
is drawing an attention in the pharmaceutical industry. This
review aims to highlight the practical value of metabolomics
in (a) potentially validating more novel therapeutic targets
and indications, (b) facilitating decision-making on the advancement
of therapeutics in the drug development process, and (c) leading
to better patient stratification and cost-effective clinical
trials, through the application of LC/MS/MRM-based targeted
metabolomics studies at a relatively low cost in pharmaceutical
companies. This paper provides a brief history of the development
of metabolomics and common strategies for conducting metabolomics
studies. The pros and cons of the most important technologies
and the major components of metabolomics studies are reviewed
and discussed. Finally, selected metabolomics study examples
are reviewed to illustrate how metabolomics can be used to
simultaneously capture underlying biochemical changes associated
with pharmaceutical interventions, and effectively produce
more accurate and/or alternative efficacy and ADR biomarkers,
thereby, greatly extending our knowledge of disease, protein
function and drug action and maximally benefiting the pharmaceutical
industry.
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Article]
Electrochemistry in the Mimicry of Oxidative Drug
Metabolism by Cytochrome P450s
E. Nouri-Nigjeh, R. Bischoff, A.P. Bruins and
H.P. Permentier
Prediction of oxidative drug metabolism at the early stages
of drug discovery and development requires fast and accurate
ana-lytical techniques to mimic the in vivo oxidation
reactions by cytochrome P450s (CYP). Direct electrochemical
oxidation combined with mass spectrometry, although limited
to the oxidation reactions initiated by charge transfer, has
shown promise in the mimicry of certain CYP-mediated metabolic
reactions. The electrochemical approach may further be utilized
in an automated manner in microfluidics devices facilitating
fast screening of oxidative drug metabolism. A wide range
of in vivo oxidation reactions, particularly those
initiated by hydrogen atom transfer, can be imitated through
the electrochemically-assisted Fenton reaction. This reaction
is based on O-O bond activation in hydrogen peroxide and oxidation
by hydroxyl radicals, wherein electrochemistry is used for
the reduction of molecular oxygen to hydrogen peroxide, as
well as the reduction of Fe3+
to Fe2+. Metalloporphyrins,
as surrogates for the prosthetic group in CYP, utilizing metallo-oxo
reactive species, can also be used in combination with electrochemistry.
Electrochemical reduction of metalloporphyrins in solution
or immobilized on the electrode surface activates molecular
oxygen in a manner analogous to the catalytical cycle of CYP
and different metalloporphyrins can mimic selective oxidation
reactions. Chemoselective, stereoselective, and regioselective
oxidation reactions may be mimicked using electrodes that
have been modified with immobilized enzymes, especially CYP
itself. This review summarizes the recent attempts in utilizing
electrochemistry as a versatile analytical and preparative
technique in the mimicry of oxidative drug metabolism by CYP.
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An Electrochemical Outlook on Tamoxifen Biotransformation:
Current and Future Prospects
J.M.P.J. Garrido, E.M.P.J. Garrido, A.M. Oliveira-Brett
and F. Borges
Tamoxifen is a nonsteroidal antiestrogen that is currently
and widely used in the treatment of breast cancer in all of
its stages, in adjuvant therapy as a long-term suppressant
of tumor recurrence and also as a chemopreventive agent in
women that are in high risk of developing this type of estrogen-dependent
cancer.
From a toxicological and (bio)analytical point of view the
knowledge of the metabolic pathways of a drug is found to
be extremely important. So, in the present work the most important
tamoxifen biotransformation steps were reviewed in the light
of recent pharmacological data. This overview also includes
the current controversy concerning tamoxifen DNA-damaging
(genotoxic) versus non-genotoxic mechanisms.
A special focus will be given to the putative application
of electrochemical methods as a modern and reliable analytical
tool for determination of tamoxifen and its metabolites. Moreover,
the potential of DNA electrochemical sensors for detection
of structural damage to DNA as a basis for toxicity screening
is highlighted.
Future prospects looking for the importance of developing
new analytical methodologies are also discussed.
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Conventional and Novel Approaches in Generating and
Characterization of Reactive Intermediates from Drugs/Drug
Candidates
H. Orhan and N.P.E. Vermeulen
Despite several thousands of drugs are in use currently,
research on new drug molecules is continuing. Because, there
are diseases still without medication, successor/better drugs
make the predecessor ones obsolete, and advancement in both
life sciences and analytical technologies provide identification
of previously unknown mechanisms of diseases, and discovery
of novel drug targets. The two main criteria which a drug
candidate should meet are high affinity for the target, and
no or acceptable/tolerable toxicity in humans. Among these
two, toxicity is the limiting one; developing a drug candidate
with unacceptable toxicity has to be discontinued, even if
it has an extremely high pharmacological activity. Drug would
be withdrawn, if serious toxicity arises after marketing.
Since drug development is a long (approximately 10 years),
expensive, and infertile (one lead in 10.000 molecules) process,
it is extremely important to detect the potential toxicity
of drug candidate as early as possible. Today, it is believed
that a great majority of toxic effects are caused by reactive
intermediates generated by biotransformation of the parent
drug. However, there are experimental difficulties in identifying
such metabolite(s) in vivo. Their formation is affected
by multi-factorial events; they can further be metabolized
to structurally different products, and/or they may bind to
a huge variety of biological sites or macromolecules. Hence,
some reactive intermediates and their corresponding stable
derivatives are generated in trace amounts, which make their
determination more difficult. The ability of cytochrome P450s
(CYP450) and other biotransformation enzymes to function in
vitro offers a great flexibility to researchers, biotransformation
of any compound can be simulated in a test tube, and metabolites/reactive
intermediates are generated in an environment which has relatively
much less background and less interfering multi-factorial
events compared to in vivo. To simulate biotransformation,
microsomal fraction is used most frequently from human and
non-human sources. Purified or recombinant enzymes are used
in determining the individual isoenzymes responsible for certain
metabolites. Because of the chemical reactivity of intermediates,
relevant, usually nucleophilic trapping agent(s) such as glutathione
(GSH), N-acetylcysteine (NAC) and cyanide (CN-) are
used to stabilize the metabolite. Trapped metabolites are
subjected to spectrometric and/or nuclear magnetic resonance
spectroscopic analyses for structural identification. Vertiginous
advances especially in mass spectrometric technologies offer
researchers new challenges in this area. This review is aimed
at briefly summarizing the state of the art and compiling
the highlighted studies in characterization of the reactive
metabolites from drug molecules.
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Matrix Metalloproteinase Inhibitors: A Review
on Bioanalytical Methods, Pharmacokinetics and Metabolism
X. Wang, K.F. Li, E. Adams and A.V.
Schepdael
Enzymes are major drug targets in drug discovery and
development processes in the pharmaceutical and biotechnology
indus-try. A recent survey found that nearly half of all the
marketed small-molecule drugs are inhibitors of enzymes. Matrix
metalloproteinases (MMPs) are a family of 28 enzymes capable
of degrading the constituents of the extracellular matrix
(ECM) and the basement-membrane. MMPs play an essential role
in several normal physiological processes including growth,
wound healing and tissue repair. Over-expression and activation
of MMPs has been linked to a range of diseases which include
osteoarthritis, tumor metastasis, angiogenesis and cardiovascular
diseases. The development of MMP inhibitors as therapeutic
agents has kept an important place in drug discovery. Therefore,
there is also an increasing need for robust analytical methods
for evaluation of inhibitory potency and for the analysis
of MMP inhibitors and their metabolites which can even play
a more significant role than the parent drug. Modern analytical
techniques and hyphenated instrumentations such as liquid
chromatography-mass spectrometry with a function of structure
elucidation can provide a profound insight into the research
of MMP inhibitors and also serve as a complementary method
to zymographic techniques for the analysis of biological samples.
This review mainly summarizes bioanalytical methods, pharmacokinetics
and related metabolites of MMP inhibitors over the last 12
years.
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