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Current
Drug Metabolism
ISSN: 1389-2002
Current Drug Metabolism
Volume 9, Number 5, June 2008
Contents:
Special Board Members Issue
Editorial Pp. 361-362
Molecular Characterization of CYP2B6 Substrates
Pp. 363-373
S. Ekins, M. Iyer, M.D. Krasowski and E.D. Kharasch
[Abstract]
The Challenges of Dealing with Promiscuous Drug-Metabolizing
Enzymes, Receptors and Transporters Pp. 374-383
Q. Ma and A.Y.H. Lu
[Abstract]
Cytochrome P450 Turnover: Regulation of Synthesis
and Degradation, Methods for Determining Rates, and Implications
for the Prediction of Drug Interactions Pp. 384-393
J. Yang, M. Liao, M. Shou, M. Jamei, K.R. Yeo, G.T. Tucker
and A. Rostami-Hodjegan
[Abstract]
An Update on Clinical Drug Interactions with
the Herbal Antidepressant St. John’s wort
Pp. 394-409
S.-F. Zhou and X. Lai
[Abstract]
Metabolism of Atypical Antipsychotics: Involvement
of Cytochrome P450 Enzymes and Relevance for Drug-Drug Interactions
Pp. 410-418
L. Urichuk, T.I. Prior, S. Dursun and G. Baker
[Abstract]
Applications and Limitations of Genetically Modified Mouse
Models in Drug Discovery and Development Pp. 419-438
J.H. Lin
[Abstract]
Liver-Enriched Transcription Factors and Their
Role in Regulating UDP Glucuronosyltransferase Gene Expression
Pp. 439-452
D.A. Gardner-Stephen and P.I. Mackenzie
[Abstract]
Heterotropic Cooperativity in Oxidation Mediated
by Cytochrome P450 Pp. 453-462
T. Niwa, N. Murayama and H. Yamazaki
[Abstract]
Abstracts
[Back to top]
Editorial
It is my great pleasure to announce that, since
its launch back in 2000, Current Drug Metabolism (henceforth
CDM), an interdisciplinary peer-reviewed journal in drug metabolism,
has successfully completed eight years of its publication
in 2007. Indexed by all major indexing media including Chemical
Abstracts, MEDLINE, BIOSIS, Science Citation Index Expanded,
etc., this cutting-edge journal is published by Bentham Science
Publishers. Bentham Science publishes more than 250 print
and open access journals (www.bentham.org), (www.bentham.org/open)
and books (www.bentham.org/ebooks).
From 2008 onwards, the journal will publish ten issues. In
a relatively short period of time, CDM has achieved an Impact
Factor of 5.762 (2006 SCI Journal Citation Reports), one of
the very highest in the field. CDM has attained eminence amongst
the most leading publications in the field of drug metabolism
and represents an important review journal of great value
to all academic, government and industrial scientists.
The journal invites contributions for both comprehensive review
articles and guest edited issues in all areas of drug metabolism
and disposition.
The journal board comprises ten Associate Editors, fifty-six
Editorial Board Members and fifty-seven Reviewers. Each Associate
Editor of CDM handles peer reviewing of papers received from
his/her region on behalf of the Editor-in-Chief. They are
also responsible for guest editing and/or soliciting a Hot
Topic issue for the journal every year on a contemporary topic
falling within the field of drug metabolism.
The journal is also publishing one issue each year dedicated
to submissions from the Editorial Board Members of CDM. This
is the first such issue and I congratulate to all the contributing
Editorial Board Members for their positive response. I strongly
believe that the support and contributions from the Editorial
Advisory Board have been thoroughly conducive to the success
of CDM. I wish to thank each of the Editorial Board Members
for their dynamic effort and contribution to this journal
and hope they will continue to serve the journal with the
same spirit.
I do hope CDM Reader find papers in this issue quite interesting:
Sean Ekins et al. describe molecular characterization
of CYP2B6 substrates. They have shown that CYP2B6 substrates
are generally small hydrophobic molecules that are frequently
central nervous system activated, which may be important for
drug discovery research.
Anthony Y. H. Lu et al. in ‘The challenges
of dealing with promiscuous drug-metabolizing enzymes, receptors
and transporters’ hypothesize that the large substrate-binding
cavities (SBCs), binding of more than one substrate/effector
and binding of substrates in alternative orientations and
locations within the SBCs, rotation of a substrate at the
active site, and substantial substrate-induced conformational
changes of the SBCs are common features of the promiscuous
drug metabolizing enzymes, receptors, and transporters, and
therefore, are important parameters to be considered in dealing
with drug metabolism issues and safety evaluation of drugs
and environmental chemicals.
Amin Rostami-Hodjegan et al. have summarized the
regulation of synthesis and degradation, methods for determining
rates, and implications of cytochrome P450 for the prediction
of drug interactions. They reviewed current understanding
of CYP regulation, discussed the pros and cons of various
in vitro and in vivo approaches used to
estimate the turnover of specific CYPs and, by simulation,
consider the impact of variability in estimates of CYP turnover
on the prediction of enzyme induction and metabolism based
inactivation (MBI) in vivo.
Shu-Feng Zhou et al. provided an update on clinical
drug interactions with the herbal anti-depressant St. John’s
wort (SJW). This review highlights and updates the knowledge
regarding drug interactions with SJW by a systematic review
of all the available evidence, including worldwide published
literature and spontaneous case reports.
In the review by Glen Baker et al., the involvement
of cytochrome P450 (CYP) enzymes in the metabolism of the
atypical (second-generation) antipsychotics clozapine, risperidone,
olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone
and amisulpride is reviewed, and the possible relevance of
this metabolism to drug-drug interactions is discussed.
Jiunn H. Lin described the applications and limitations of
genetically modified mouse models in drug discovery and development.
Genetically modified mouse models in which a specific gene
is removed or replaced have proven to be powerful tools for
the identification/validation of target gene and scientific
understanding of molecular mechanisms underlying drug-induced
toxicity through mechanistic studies. Although the creation
of humanized animals that carry a particular human CYP
gene provides useful tools for scientific understanding of
the function and regulation of CYP enzymes, these humanized
mouse models are not so useful in the prediction of human
pharmacokinetics in a quantitative sense.
P.I. Mackenzie et al. described what is currently
known about the Liver-Enriched Transcription Factors (LETFs),
including Hepatocyte Nuclear Factors 1 and 4a, and their role
in UGT gene expression. It is likely that polymorphisms in
LETFs and the sites to which they bind in UGT genes, may impact
on drug induced disease and drug therapy.
Hiroshi YAMAZAKI et al. provided an overview of the
heterotropic cooperativity in the oxidation mediated by cytochrome
P450 along with presenting a few cases of the cooperativity
of CYP3A in experimental animals.
As the Editor-in-Chief, I wish Current Drug Metabolism will
continue to provide a forum for the in-depth discussions on
latest developments in the drug metabolism field. Last but
not least, the concerted efforts of the Bentham Science Editorial
Office in managing CDM affairs are highly appreciated.
*Dr. Prakash obtained his Ph.D. in organic chemistry in
1977. He held several academic appointments the last of which
as Research Associate Professor and Associate Director of
Mass Spectrometry resources at Vanderbilt University. He joined
Pfizer Global Research and Development in 1992 as a Senior
Research Investigator in the department of Pharmacokinetics,
Dynamics and Metabolism (PDM). He was promoted to Principal
Research Investigator (1996), Research Advisor (2000) and
Research Fellow (2004).
Dr. Prakash has been involved in the drug metabolism studies
to support drug discovery, development and registration. His
work is focused on the development of approaches and techniques
for the rapid identification of drug metabolites and the prediction
of human circulating metabolites based on in vitro and preclinical
studies. His research interests include application of LC-MS
and radio detection techniques, development of chemical model
to mimic CYP metabolic activities, metabolic bioactivation,
and reaction phenotyping of metabolizing enzymes to facilitate
the discovery and development of new chemical entities as
drug candidates. He is the author of more than 200 manuscripts,
book chapters, abstracts and patents. He reviews extensively
for a number of scientific journals and serves as the Editor-in-Chief
of the Journals “Current Drug Metabolism” and
"Drug Metabolism Letters". He is also on the editorial
board of the journal "Expert Opinion on Drug Metabolism
& Toxicology". Dr. Prakash is a member of American
Society for Pharmacology and Experimental Therapeutics, American
Society of Mass Spectrometry and Allied Topics, International
Society for the Study of Xenobiotics, Asian Federation of
Clinical Pharmacologist and New York Academy of Science.
CHANDRA PRAKASH, Ph.D
Editor-in-Chief, Current Drug Metabolism
Research Fellow
Global Research and Development
Pfizer, Inc., Eastern Point Road
Groton, CT 06340
USA
[Back to top]
Molecular Characterization of CYP2B6 Substrates
S. Ekins, M. Iyer, M.D. Krasowski and E.D. Kharasch
CYP2B6 has not been as fully characterized at the molecular
level as other members of the human cytochrome P450 family.
As more widely used in vitro probes for characterizing
the involvement of this enzyme in the metabolism of xenobiotics
have become available, the number of molecules identified
as CYP2B6 substrates has increased. In this study we have
analyzed the available kinetic data generated by multiple
laboratories with human recombinant expressed CYP2B6 and along
with calculated molecular properties derived from the ChemSpider
database, we have determined the molecular features that appear
to be important for CYP2B6 substrates. In addition we have
applied 2D and 3D QSAR methods to generate predictive pharmacophore
and 2D models. For 28 molecules with Km data, the molecular
weight (mean ± SD) is 253.78±74.03, ACD/logP
is 2.68±1.51, LogDph
5.5 is 1.51±1.43,
LogDph 7.4
is 2.02±1.25, hydrogen bond donor (HBD) count is 0.57
±0.57, hydrogen bond acceptor (HBA) count is 2.57±1.37,
rotatable bonds is 3.50±2.71 and total polar surface
area (TPSA) is 27.63±19.42. A second set of 15 molecules
without Km data possessed
similar mean molecular property values. These properties are
comparable to those of a set of 21 molecules used in a previous
pharmacophore modeling study (Ekins et al., J Pharmacol
Exp Ther 288 (1), 21-29, 1999). Only the LogD and HBD values
were statistically significantly different between these different
datasets. We have shown that CYP2B6 substrates are generally
small hydrophobic molecules that are frequently central nervous
system active, which may be important for drug discovery research.
[Back to top]
The Challenges of Dealing with Promiscuous Drug-Metabolizing
Enzymes, Receptors and Transporters
Q. Ma and A.Y.H. Lu
Unlike classical enzymes, drug-metabolizing enzymes (DMEs),
such as the liver microsomal cytochrome P450, UDP-glucuronyltransferase,
epoxide hydrolase, and flavin-containing monooxygenase, all
exhibit broad substrate specificities, low turnover rates,
atypical kinetics, and other unusual properties. Receptors
(the pregnane X receptor, NR1I2; the constitutive androstane
receptor, NR1I3; and the aromatic hydrocarbon receptor) responsible
for the induction of DMEs and transporters (P-glycoprotein)
responsible for drug transport also have broad substrate specificities.
These promiscuous proteins are all intimately involved in
drug disposition. Promiscuous proteins, by definition, are
known for diversity, but not specificity, in their interaction
with drugs. In this review, we analyzed recent advances on
the three dimensional structures and kinetic properties of
DMD proteins from crystallography, mutational, and kinetic
studies to gain insights into the structural and biochemical
basis for the promiscuous ligand-protein interactions of the
proteins. Large substrate-binding cavities (SBCs), binding
of more than one substrate/effector and binding of substrates
in alternative orientations and locations within the SBCs,
rotation of a substrate at the active site, and substantial
substrate-induced conformational changes of the SBCs are common
features of the promiscuous DMEs, receptors, and transporters,
and therefore, are important parameters to be considered in
dealing with drug metabolism issues and safety evaluation
of drugs and environmental chemicals.
[Back to top]
Cytochrome P450 Turnover: Regulation of Synthesis and Degradation,
Methods for Determining Rates, and Implications for the Prediction
of Drug Interactions
J. Yang, M. Liao, M. Shou, M. Jamei, K.R. Yeo, G.T. Tucker
and A. Rostami-Hodjegan
In vivo enzyme levels are governed by the rates of de
novo enzyme synthesis and degradation. A current lack of consensus
on values of the in vivo turnover half-lives of human
cytochrome P450 (CYP) enzymes places a significant limitation
on the accurate prediction of changes in drug concentration-time
profiles associated with interactions involving enzyme induction
and mechanism (time)-based inhibition (MBI). In the case of
MBI, the full extent of inhibition is also sensitive to values
of enzyme turnover half-life. We review current understanding
of CYP regulation, discuss the pros and cons of various
in vitro and in vivo approaches used to estimate
the turnover of specific CYPs and, by simulation, consider
the impact of variability in estimates of CYP turnover on
the prediction of enzyme induction and MBI in vivo.
In the absence of consensus on values for the in vivo
turnover half-lives of key CYPs, a sensitivity analysis of
predictions of the pharmacokinetic effects of enzyme induction
and MBI to these values should be an integral part of the
modelling exercise, and the selective use of values should
be avoided.
[Back to top]
An Update on Clinical Drug Interactions with the Herbal Antidepressant
St. John’s wort
S.-F. Zhou and X. Lai
St. John's wort (Hypericum perforatum, SJW)
is one of the most commonly used herbal antidepressants for
the treatment of minor to moderate depression. Limited clinical
trials suggest that hypericum and standard antidepressants
have similar beneficial effects, but current evidence regarding
the antidepression effects of SJW extracts is inconsistent.
A major safety concern about SJW is its ability to alter the
pharmacokinetics and/or clinical response of a variety of
clinically important drugs. This review highlights and updates
the knowledge regarding drug interactions with SJW by a systematic
review of all the available evidence, including worldwide
published literature and spontaneous case reports. A number
of clinically significant interactions of SJW have been identified
with conventional drugs. These interactions often result in
a decrease in the concentration or effect of the combined
drug, most probably due to the induction of cytochrome P450s
(CYPs) and the key drug transporter P-glycoprotein (P-gp)
by the major active constituents in SJW. SJW is a potent inducer
of human CYP3A4 and P-gp in vitro and in vivo.
In addition, pharmacodynamic interactions of SJW with some
drugs (e.g. selective serotonin re-uptake inhibitors) have
been identified, which are associated with an increased risk
of adverse reactions. Since potential interactions of SJW
with conventional drugs is a major safety concern, it is important
to minimize and avoid these interactions by taking appropriate
approaches. These include systematic research to identify
SJW-drug interaction; close therapeutic drug monitoring when
SJW is combined with conventional drugs with a narrow therapeutic
window; proper dose and regimen adjustment; patient education
and communication between the patient and physician; design
of new preparations of SJW without inducing ability of CYP3A4
and P-gp while retaining its bioactivity; and appropriate
regulation in herbal safety and efficacy. Further clinical
and mechanistic studies are warranted to explore the interaction
of SJW with other important drugs and clinical significance.
[Back to top]
Metabolism of Atypical Antipsychotics: Involvement of Cytochrome
P450 Enzymes and Relevance for Drug-Drug Interactions
L. Urichuk, T.I. Prior, S. Dursun and G. Baker
The involvement of cytochrome P450 (CYP) enzymes
in the metabolism of the atypical (second-generation) antipsychotics
clozapine, risperidone, olanzapine, quetiapine, ziprasidone,
aripiprazole, paliperidone and amisulpride is reviewed, and
the possible relevance of this metabolism to drug-drug interactions
is discussed.
Clozapine is metabolized primarily by CYP1A2, with additional
contributions by CYP2C19, CYP2D6 and CYP3A4. Risperidone is
metabolized primarily by CYP2D6 and to a lesser extent by
CYP3A4; the 9-hydroxy metabolite of risperidone (paliperidone)
is now marketed as an antipsychotic in its own right. Olanzapine
is metabolized primarily by direct glucuronidation and CYP1A2
and to a lesser extent by CYP2D6 and CYP3A4. Quetiapine is
metabolized by CYP3A4, as is ziprasidone, although in the
latter case aldehyde oxidase is the enzyme responsible for
most of the metabolism. CYP2D6 and CYP3A4 are important in
the metabolism of aripiprazole, and CYP-catalyzed metabolism
of paliperidone and amisulpride appears to be minor. At the
usual clinical doses, these drugs appear to not generally
affect markedly the metabolism of other coadministered medications.
However, as indicated above, several of atypical antipsychotics
are metabolized by CYP enzymes, and physicians should be aware
of coadministered drugs that may inhibit or induce these CYP
enzymes; examples of such possible interactions are presented
in this review.
[Back to top]
Applications and Limitations of Genetically Modified Mouse
Models in Drug Discovery and Development
J.H. Lin
Genetically modified mouse models in which a specific
gene is removed or replaced have proven to be powerful tools
for identification/validation of target gene and scientific
understanding of molecular mechanisms underlying drug-induced
toxicity through mechanistic studies. In spite of the advantage,
there are significant limitations of genetically modified
mouse models. Modification of a given gene does not always
result in the anticipated phenotype. In some instances, phenotypes
of targeted mouse mutants were not those predicted from the
presumed function of the given genes, while other null mutants
revealed no apparent defects. Furthermore, the phenotypic
outcome can be influenced by many environmental and genetic
factors. Therefore, interpretation of the significance of
the findings from studies using genetically modified mouse
models is not always as straightforward as one would expect,
especially when desire is to extrapolate the findings to humans.
Interestingly, many humanized mouse models have been generated
for evaluating the function and regulation of cytochrome P450
(CYP) enzymes. Our fascination with humanized animals dates
back to ancients. For example, the Great Sphinx of Giza, a
large half-human and half-lion statue, is believed to have
been built by Egyptians about 4500 years ago. Although the
creation of humanized animals that carry a particular human
CYP gene provides useful tools for scientific understanding
of the function and regulation of the CYP enzyme, these humanized
mouse models are not so useful in prediction of human pharmacokinetics
in a quantitative sense. Accordingly, it is important to keep
in mind that an animal engineered to express a human gene
and its protein is still an animal.
[Back to top]
Liver-Enriched Transcription Factors and Their Role in Regulating
UDP Glucuronosyltransferase Gene Expression
D.A. Gardner-Stephen and P.I. Mackenzie
Variations in the capacity to detoxify carcinogens and
other environmental toxins, and to eliminate drugs and waste
products of metabolism, are likely to have significant effects
on health and drug efficacy. As the UDP glucuronosyltransferases
metabolize many of these substances to less toxic glucuronides,
variations in UGT expression are likely to be important in
maintenance of health and therapeutic outcomes. The factors
that regulate UGT gene expression are beginning to be identified.
From among these factors, the Liver-Enriched Transcription
Factors (LETFs), including Hepatocyte Nuclear Factors 1 and
4α
, have a major role in UGT regulation in the major sites of
drug metabolism, the liver and gastrointestinal tract. This
review will describe what is currently known about these LETFs
and their role in UGT gene expression. It is likely that polymorphisms
in LETFs and the sites to which they bind in UGT genes, may
impact on drug induced disease and drug therapy.
[Back to top]
Heterotropic Cooperativity in Oxidation Mediated by Cytochrome
P450
T. Niwa, N. Murayama and H. Yamazaki
Cytochrome P450s (P450 or CYPs) comprise a superfamily
of enzymes that catalyze the oxidation of a wide variety of
xenobiotic chemicals. Although most of P450 inhibitors decrease
the metabolic activities mediated by the corresponding P450
forms, unexpected phenomena, which are called as activation
or heterotropic cooperativity, have been often observed. We
summarize Michaelis-Menten constants (Km),
maximal velocities (Vmax),
Vmax / Km
(intrinsic clearance) values, and/or metabolic activities
for 22 activators and 24 substrates (30 reactions) mainly
mediated by CYP3A4 among human P450 forms. Although an allosteric
mechanism has been invoked to explain the cooperativity, the
activation patterns or phenomena are dependent on substrates
and selected enzyme sources in vitro. Interestingly,
recent studies have been shown that human P450 forms other
than CYP3A4, such as CYP1A2, CYP2C8, CYP2C9, CYP2D6, and CYP3A7,
are also activated by some compounds, whereas there are few
reports on CYP3A5. Several models describing interaction among
substrates, effectors, and enzymes have been proposed, however,
the detailed mechanism for the activation is still generally
unknown even though some crystal structures have been shown.
A few cases of the cooperativity of CYP3A in experimental
animals have been presented, whereas the clinical significance
of P450 cooperativity is still unclear. The collective findings
provide fundamental and useful information for the activation
of P450s by chemicals despite some contradictive kinetic parameters
for the same reactions reported. To understand causal factor(s)
and mechanism(s) for such different reports summarized here
is still one of the hot research topics to be solved in current
activation reactions.
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