13

DETERMINATION OF METABOLIC

RATES AND ENZYME KINETICS

ZHI-YIZHANG ANDLAURENCES. KAMINSKY

13.1 INTRODUCTION

In vitrobiochemical studies of drug metabolism, particularly studies associated
with pharmacokinetic (PK) properties and potential toxicological conse-
quences, are essential in drug discovery and development. For over a decade,
the major pharmaceutical companies have been promoting such efforts for
incorporation into early stages in discovery (Obach, 2001; Smith and van de
Waterbeemd, 1999). Consequently, the failure rate of new chemical entities
(NCEs) due to absorption, distribution, metabolism, and excretion (ADME)
shortcomings in clinical trials, in contrast to some of the other major hurdles
including poor efficacy and intolerable toxicity, has continuously decreased
(Apic et al., 2005).
Studies of metabolic stability were integrated into critical paradigms in all
discovery phases, particularly during early lead identification and optimization.
The nature of discovery demands that such metabolism studies at these early
stages be conducted with short turnaround times, and the studies should be
simple rather than comprehensive and thus less time consuming. Metabolism is
usually only expressed as the intrinsic clearance (CLint), or as disappearance or
half-life (t1/2). Characterization of biotransformation, enzyme-kinetically, is the
main theme for metabolic studies during preclinical development, as opposed
to discovery. Thein vitrokinetic parameters, including those directly used for
the selections of incubation condition in enzyme reaction phenotyping and the

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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