15 Reaction Phenotyping
SUSANHURST,J.ANDREWWILLIAMS,ANDSTEVENHANSEL
15.1 INTRODUCTION
Consistent, predictable efficacy, and safety are desired for today’s pharma-
ceutical agents. Since these attributes typically correlate with a drug’s systemic
exposure, gaining an understanding of contributors to unacceptably risky
interindividual pharmacokinetic variability may permit enhanced disease
management as well as offer insight into the design of newer, more desirable
clinical agents. Sources of potentially significant interindividual pharmacoki-
netic variation include interacting comedications, polymorphic expression of
dispositional metabolizing enzymes or transporters, and dietary influences.
This chapter will focus on the practical application of human drug metabolism
reaction phenotyping strategies andin vitro techniques as they pertain to
understanding a drug’s metabolic processing via cytochrome P450 (CYPs) and
noncytochrome P450 enzyme systems, including conjugation. A brief
consideration of the emerging understanding of transporter phenotypic
influence upon drug disposition is also included.
Drug metabolism reaction phenotyping by definition is the estimation of
the relative contributions of specific enzymes to the metabolism of a test
compound (Williams et al., 2005). Such studies may take the form ofin vitroor
in vivo assessment using a variety of approaches and tools and can be
strategically employed at points along the drug discovery, drug development,
and postlaunch continuum. An increased understanding of the clinical
significance of how certain drug metabolizing enzymes contribute to
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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