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Mechanism-Based Inactivation of Cytochrome P450 Enzymes: Chemical Mechanisms, Structure-Activity Relationships and Relationship to Clinical Drug-Drug Interactions and Idiosyncratic Adverse Drug Reactions

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Cytochrome P450 constitute a superfamily of heme-containing enzymes that catalyze the oxidative biotransformation of structurally diverse xenobiotics including drugs. Inhibition of P450 enzymes is by far the most common mechanism which can lead to DDIs. P450 inhibition can be categorized as reversible (competitive or non-competitive) or irreversible (mechanism-based inactivation). Mechanism-based P450 inactivation usually involves bioactivation of the xenobiotic to a reactive intermediate, which covalently modifies an active site amino acid residue and/or coordinates to the heme prosthetic group. Covalent modification of P450 enzymes can also lead to hapten formation and can in some cases trigger an autoimmune response resulting in toxicological consequences. Compared to reversible inhibition, irreversible inhibition more frequently results in unfavorable DDIs as the inactivated P450 enzyme has to be replaced by newly synthesized protein. For these reasons, most drug metabolism groups within pharmaceutical companies have well-established screening paradigms to assess mechanism-based inactivation of major human P450 enzymes by new chemical entities followed by indepth mechanistic studies to elucidate the mechanism of P450 inactivation when a positive finding is discerned. A deeper understanding of the process leading to enzyme inactivation by drug candidates can lead to rational chemical intervention strategies to circumvent the P450 inactivation/bioactivation liability. Apart from structure-activity relationship studies, methodology to predict the magnitude of in vivo metabolic DDIs using in vitro P450 inactivation data and predicted human pharmacokinetics of the candidate drug also exists and can be utilized to project the extent of clinical DDIs against P450 enzyme-specific substrates. In this review, a comprehensive analysis of the biochemical basis and known structure-activity relationships for P450 inactivation by xenobiotics is described. In addition, the current state-of-the-art of the methodology used in predicting the magnitude of DDIs using in vitro P450 inactivation data and human pharmacokinetic parameters is discussed in detail.

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Keywords: Cytochrome P450; MI complex; apoprotein; glutathione; heme; hepatotoxicity; inhibitor; mechanism-based inactivation; reactive metabolite; xenobiotic

Document Type: Research Article

Publication date: June 1, 2007

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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