7

REGULATORY CONSIDERATIONS

OF DRUG METABOLISM AND DRUG

INTERACTION STUDIES

XIAOXIONGWEI ANDMINGSHEZHU

7.1 INTRODUCTION

Historically, drug metabolism research in the pharmaceutical industry
concentrated on radiolabeled absorption, distribution, metabolism, and
excretion (ADME) studies in humans and preclinical species. These studies
were conducted in the late phase of drug development mainly for supporting
new drug regulatory registration. In the late 1990s, regulatory guidances on
drug metabolism and drug–drug interactions (DDI) were issued by the
regulatory authorities in the United States (FDA, 1997, 1999) and Europe,
which define the role and practice of the contemporary drug metabolism in
drug development and registration. Since then, drug metabolism research in
the industry has focused on to earlyin vitroassessment of potential DDI of
drug candidates, including screening of CYP enzyme inhibition and induction,
and reaction phenotyping of metabolizing enzymes. Consequently, the drug
metabolism organization or function within industry was rapidly extended to
drug discovery, and ultimately drug metabolism has become a vital and
integrated part of the drug discovery and development process (Kola and
Landis, 2004; Smith et al., 2002). In 2005, the US Food and Drug
Administration (FDA) published a draft guidance entitled ‘‘Safety Testing of
Drug Metabolites’’ (FDA, 2005b). This guidance emphasizes the critical role of
animal and human ADME studies in the selection of metabolites for

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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