8

DRUG METABOLISM RESEARCH AS

AN INTEGRAL PART OF THE DRUG

DISCOVERY PROCESS

W. GRIFFITHHUMPHREYS

8.1 INTRODUCTION

Drug metabolism research has become an integral part of the lead optimization
phase of drug discovery. The goal of this work is to attempt to optimize the
metabolism properties of clinical candidates in parallel with the optimization of
the potency and efficacy. The major reason to optimize the metabolism of a
new chemical entity is so the clearance properties can be matched to the
indication. For most indications involving chronic, oral therapy that means
that compounds must be found with preclinical clearance properties that
predict a human clearance consistent with qd administration (this is not true in
all cases, some indications may require a short duration of action and thus
rapid metabolism). Drugs that have rapid metabolic clearance and low
percentage of absolute oral bioavailability (%F) due to high preabsorptive and
first-pass metabolism are likely to have a high degree of inter and intrapatient
variability (Hellriegel et al., 1996) and be more likely to suffer from drug–drug
interactions. Also, drugs with rapid clearance and low %F are likely to require
suboptimal dosing regimes, that is, bid or tid, and/or relatively high doses. The
former leads to poor patient compliance, suboptimal efficacy, and marketing
issues and the later can lead to unanticipated toxicities due to a large flux of
drug and drug metabolites. Other benefits to understanding and optimizing the
metabolism of new chemical entity (NCEs) are

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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