Current Drug Metabolism - Volume 9, Issue 5, 2008

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......

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.

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.

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.

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.

The involvement of cytochrome P450 (CYP) enzymes in the metabolism of the atypical (secondgeneration) 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.

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.

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.

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.