16

ANALYSIS OF IN VITRO

CYTOCHROME P450 INHIBITION

IN DRUG DISCOVERY

AND DEVELOPMENT

MAGANGSHOU ANDRENKEDAI

16.1 INTRODUCTION

Investigation of the inhibition potential of drugs or drug candidates toward
human drug metabolizing enzymes (DMEs), particularly hepatic cytochromes
P450 (CYPs) is of great interest to pharmaceutical scientists and clinicians. In
the pharmaceutical industry,in vitroscreening of CYP enzyme inhibition of
new chemical entities (NCEs) provides critical information for lead finding,
optimization of drug candidates and evaluation of drug–drug interaction
potential in humans (Bjornsson et al., 2003; Ito et al., 1998; Lin, 2000; Lin and
Lu, 2001; Obach 2003; Obach et al., 2005; Obach et al., 2006; Shou 2005). A
metabolism-based drug interaction implies that one drug causes a change in the
metabolic clearance of another drug, in turn either decreasing or increasing
concentrations of the drug in plasma, and presumably also causes a change at
the site of action, that has led and can lead to either pharmacodynamic (PD)
inhibition or enhancement of the clinical effects or serious toxicological
consequences of another drug in human (Backman et al., 1994; Gomez et al.
1995; Gorski et al., 1998; Greenblatt et al., 1998a, 1998b, 1999; Heerey et al.,
2000, 1993a, 1993b, 1993c; Honig and Cantilena 1994; Olkkola et al., 1994;

Drug Metabolism in Drug Design and Development, Edited by Donglu Zhang, Mingshe Zhu
and W. Griffith Humphreys
Copyright#2008 John Wiley & Sons, Inc.

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