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Enzyme Kinetics for Clinically Relevant CYP Inhibition

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In vitro cytochrome P450 (CYP)-associated metabolic studies have been considered cost-effective for predicting the potential clinical drug-drug interactions (DDIs), one of the major attritions in drug development. The breakthroughs during the past decade in understanding the biochemistry of CYP-mediated biotransformation and molecular biology of CYP gene regulation in humans have provided the scientific bases for such endeavors in early drug development.

In this review, the enzyme kinetics of CYP inhibitions is described, with the primary focus on the ones proven with clinical relevance, namely the competitive inhibition and mechanism-based inactivation (MBI). Competitive CYP inhibition, the most often detected reversible inhibition, is well understood and has been studied extensively both in vitro and in clinical setting. Recently, MBI has received increasing attention. It has been recognized that MBI could occur more often than anticipated, due in part to the redox cycling-allied enzymatic action of CYPs. As commonly as an irreversible inhibition, MBI would inactivate the target proteins, and thus would be generally considered of high potential for causing clinical DDI. Moreover, the reversible inhibitions other than the competitive, namely noncompetitive, uncompetitive and mixed, were also documented for the important drug-metabolizing CYP members, particularly CYP1A2 and CYP2C9. Finally, the unusual kinetic interactions, which did not follow the Michaelis-Menten (M-M) kinetics, were detected in vitro for the majority of drug-metabolizing CYP members, and manifested for CYP3A4. However, the clinical relevance of the interactions involving the unusual CYP kinetics has not yet been fully understood. Nonetheless, the reversibility and inhibitory potency should be considered as the major determinants of the clinical relevance, particularly in combination with the therapeutic exposure levels. With rapid expansion of knowledge and technology, the evaluation of the clinically relevant CYP-associated DDIs in vitro is not only desirable but also achievable.
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Keywords: atypical kinetics; cytochrome p; drug-drug interaction; enzyme inhibition; in vitro-in vivo correlation; mechanism-based inactivation; pharmacokinetics and clinic

Document Type: Review Article

Affiliations: Eisai Research Institute, Drug Disposition, 100 Research Drive, Wilmington, MA 01887.

Publication date: June 1, 2005

More about this publication?
  • Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:

    In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.
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