9

ROLE OF DRUG METABOLISM

IN DRUG DEVELOPMENT

RAMASWAMYIYER ANDDONGLUZHANG

9.1 INTRODUCTION TO THE ROLE OF DRUG METABOLISM

IN DRUG DEVELOPMENT

In drug discovery, metabolism studies are conducted to select compounds with
superior absorption, distribution, metabolism, and excretion (ADME) proper-
ties and to eliminate compounds with potential liabilities. In drug development,
metabolism studies are conducted to provide detailed data about the disposition
of the selected compounds in animals and humans. Metabolism studies in the
early drug discovery stages often involve evaluating a series of compounds with
the main purpose of selecting a compound with high metabolic stability;
multiple clearance pathway; low potential for enzyme inhibition or induction,
and, finally, low potential for forming reactive intermediates. Once the
compound is selected for clinical development, then detailed studies, often
with radiolabeled compound, are conducted during the drug development
process in animals (toxicology species) and humans to predict potential drug–
drug interactions, help address safety issues and provide data for registration.
The focus of this chapter is on the role of drug metabolism in drug development.

9.1.1 Drug Metabolism and Clinical Interactions

Absorption, distribution, metabolism, and excretion are four key processes
that determines exposure and duration of a drug’s activity. Understanding

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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