In Vitro Cytochrome P450 Inhibition and Induction

Robert   L.   Walsky; Sherri   E.   Boldt

doi:10.2174/138920008786485128

Abstract

The assessment of in vitro inhibition and induction of the cytochrome P450 enzymes of the liver is a critical part of the drug discovery and development process in order to ensure that two or more drugs can be safely coadministered without alterations in exposure. Early assessment of potential candidates using high throughput approaches provides key direction in choosing the most promising chemical series to pursue. In later stage development, the use of in vitro data to assess the potential for clinical interactions is now a practice readily accepted by regulatory authorities. Inhibition of drug metabolizing enzymes can occur via two principal mechanisms, reversible inhibition and time dependent inhibition (mechanism-based inactivation). Clinically, either of these mechanisms can lead to reduced clearance of a coadministered drug and potentially toxic levels may be reached. Inducers of a drug metabolizing enzyme can increase the clearance of other drugs, or itself, resulting in a decreased therapeutic effect; they can also increase the bioactivation of drugs that can produce reactive intermediates, leading to hepatotoxicity. A number of in vitro models composed of human-derived microsomes, recombinantly expressed human drug metabolizing enzymes, human-derived cell lines, as well as fresh and cryopreserved human hepatocytes, are increasingly in use to evaluate inhibition and induction. In this review, the authors understanding of currently utilized enzyme inhibition and induction methodologies are presented and the authors provide recommendations regarding which assay types offer the greatest advantage during the drug development process.

Keywords: Time dependent inhibition, mechanism-based inactivation, inhibition, induction, cytochrome P450, mass spectrometry, in vitro, hepatocyte