Drugs as CYP3A Probes, Inducers, and Inhibitors

Liu, Yitong; Hao, Haiping; Liu, Changxiao; Wang, Guangji; Xie, Hong‐Guang

doi:10.1080/03602530701690374

Cited by 178 publications

(101 citation statements)

References 117 publications

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“…Hence, maintaining the required minimal tacrolimus trough concentrations in patients who express CYP3A5 variants *1/*1 and *1/*3 requires approximately twice the dose compared with patients with the *3/*3 (inactive) genotype (Iwasaki, 2007). Given the significant overlap in substrate specificity between CYP3A5 and CYP3A4, which share 84% similarity of their amino acid sequences (Liu et al, 2007), identification of a suitable in vitro tool to distinguish the enzymatic contributions of each CYP3A isoform has been problematic. As such, the ability to predict the clinical impact of the CYP3A5 genotype on the pharmacokinetics of a CYP3A substrate has suffered too.…”

Section: Discussion Cytochrome P450smentioning

confidence: 99%

Reaction Phenotyping: Advances in the Experimental Strategies Used to Characterize the Contribution of Drug-Metabolizing Enzymes

2014

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During the process of drug discovery, the pharmaceutical industry is faced with numerous challenges. One challenge is the successful prediction of the major routes of human clearance of new medications. For compounds cleared by metabolism, accurate predictions help provide an early risk assessment of their potential to exhibit significant interpatient differences in pharmacokinetics via routes of metabolism catalyzed by functionally polymorphic enzymes and/or clinically significant metabolic drug-drug interactions. This review details the most recent and emerging in vitro strategies used by drug metabolism and pharmacokinetic scientists to better determine rates and routes of metabolic clearance and how to translate these parameters to estimate the amount these routes contribute to overall clearance, commonly referred to as fraction metabolized. The enzymes covered in this review include cytochrome P450s together with other enzymatic pathways whose involvement in metabolic clearance has become increasingly important as efforts to mitigate cytochrome P450 clearance are successful. Advances in the prediction of the fraction metabolized include newly developed methods to differentiate CYP3A4 from the polymorphic enzyme CYP3A5, scaling tools for UDP-glucuronosyltranferase, and estimation of fraction metabolized for substrates of aldehyde oxidase. IntroductionIn an era where combination drug therapy to treat several conditions simultaneously is common, drug companies emphasize the need for optimal absorption, distribution, metabolism, and excretion (ADME) properties, with the purpose of optimization of efficacy and minimization of the risk of adverse events. This includes a proper assignment and an extensive understanding of the routes of metabolism to aid in the prediction of human pharmacokinetics, and to help avoid a potential "object drug" scenario when coadministration is likely. The attributes of the coadministered drug and/or the patient has the potential to increase the probability of a drug-drug interaction (DDI), i.e., enzyme inhibitor, inducer, polymorphic genotype. Hence, the greater the percentage attributed to a single metabolic route, the greater the potential for a DDI and possible "black box warning" being issued as part of the drug package insert. Furthermore, the pharmacokinetic implications of a single polymorphic enzyme being responsible for a majority of the metabolism of a drug may have either an efficacy (extensive metabolizers) or toxicological (poor metabolizers) impact on exposure. To address these concerns, early drug discovery teams strive for balanced metabolism across multiple enzymes and clearance mechanisms (hepatic, renal, biliary). These discovery efforts center on in vitro reaction phenotyping to support enhanced chemical design.There is a general agreement among the major regulatory agencies that pharmaceutical companies should provide a characterization of the metabolic profile of a new chemical entity (NCE) and understand the enzymology of the major clearance mechanisms ...

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Section: Discussion Cytochrome P450smentioning

confidence: 99%

Reaction Phenotyping: Advances in the Experimental Strategies Used to Characterize the Contribution of Drug-Metabolizing Enzymes

2014

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“…Cytochromes P450 (P450s) are major metabolizing enzymes involved in the clearance of a large number of drugs (Liu et al, 2007). Inhibition of P450 enzymes by coadministered drugs can lead to overexposure and has been attributed to the withdrawal of several drugs from the market, of which mibefradil is one example (Krayenbuhl et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

CYP3A Time-Dependent Inhibition Risk Assessment Validated with 400 Reference Drugs

Zimmerlin

Trunzer²,

Faller³

2011

Drug Metab Dispos

104

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ABSTRACT:Although reversible CYP3A inhibition testing is well established for predicting the drug-drug interaction potential of clinical candidates, time-dependent inhibition (TDI) has become the focus of drug designers only recently. Failure of several late-stage clinical candidates has been attributed to TDI, and this mechanism is also suspected to play a role in liver toxicities often observed in preclinical species. Measurement of enzyme inactivation rates (k inact and K I ) is technically challenging, and a great deal of variability can be found in the literature. In this article, we have evaluated the TDI potential for 400 registered drugs using a high-throughput assay format based on determination of the inactivation rate (k obs ) at a single concentration of test compound (10 M). The advantages of this new assay format are highlighted by comparison with data generated using the IC 50 shift assay, a current standard approach for preliminary assessment of TDI. With use of an empirically defined positive/negative k obs bin of 0.02 min ؊1, only 4% of registered drugs were found to be positive. This proportion increased to more than 20% when in-house lead optimization molecules were considered, emphasizing the importance of identifying this property in selection of promising drug candidates. Finally, it is suggested that the data and technology described here may be a good basis for building structure-activity relationships and in silico modeling.

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“…[3] Finally, the frequency of CYP3A5*3 which is decreased activity allele also showed ethnic differences; Vietnamese-Koreans (78.4%), AfricanAmericans (32%), Caucasians (90-93%), Hispanics (65%), and South Asians (60%). [36,37] There are some limitations of the present study. First, only few Vietnamese-Korean subjects were genotyped for this study because it was hard to enroll that population.…”

Section: Transl Clin Pharmacolmentioning

confidence: 93%

Genetic polymorphisms of CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 in Vietnamese-Koreans

Lim

Cha

Jung

et al. 2014

Transl Clin Pharmacol

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Drugs as CYP3A Probes, Inducers, and Inhibitors

Cited by 178 publications

References 117 publications

Reaction Phenotyping: Advances in the Experimental Strategies Used to Characterize the Contribution of Drug-Metabolizing Enzymes

Reaction Phenotyping: Advances in the Experimental Strategies Used to Characterize the Contribution of Drug-Metabolizing Enzymes

CYP3A Time-Dependent Inhibition Risk Assessment Validated with 400 Reference Drugs

Genetic polymorphisms of CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 in Vietnamese-Koreans

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