Assessment of Cytochrome P450 Enzyme Inhibition and Inactivation in Drug Discovery and Development

David      O. Nettleton; Heidi      J. Einolf

Abstract

Evaluation of the potential of a drug candidate to inhibit or inactivate cytochrome P450 (CYP) enzymes remains an important part of pharmaceutical drug Discovery and Development programs. CYP enzymes are considered to be one of the most important enzyme families involved in the metabolic clearance of the vast majority of prescribed drugs. Clinical drug-drug interactions (DDI) involving inhibition or time-dependent inactivation of these enzymes can result in dangerous side effects resulting from reduced clearance/increased exposure of the drug being affected (the ‘victim’ drug). In this regard, pharmaceutical companies have become quite vigilant in mitigating CYP inhibition/inactivation liabilities of drug candidates early in Discovery including continued risk assessment throughout Development. In this review, common strategies and decision making processes for the assessment of DDI risk in the different stages of pharmaceutical development are discussed. In addition, in vitro study designs, analysis, and interpretation of CYP inhibition and inactivation data are described in stage appropriate context. The in vitro tools and knowledge available now enable the Discovery Chemist to place the potential CYP DDI liability of a drug candidate into perspective and to aid in the optimization of chemical drug design to further mitigate this risk.

Keywords: CYP, Cytochrome P450, drug-drug interaction, inactivation, inhibition, time-dependent inactivation

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