10

APPLICATIONS OF LIQUID

RADIOCHROMATOGRAPHY

TECHNIQUES IN DRUG

METABOLISM STUDIES

MINGSHEZHU,WEIPINGZHAO,ANDW. GRIFFITHHUMPHREYS

10.1 INTRODUCTION

Radioactive isotopes are routinely used to trace the fate of drugs in disposition
and metabolism studies conducted during drug discovery and development
(Dalvie, 2000; Marathe et al., 2004; Veltkamp, 1990). Most studies involving
radioactive compounds use either^3 Hor^14 Cto replace an H or C atom of the
original drug molecule.^3 H-labeled compounds that can be readily prepared in
most cases are primarily used for investigative metabolism and selected
biotransformation studies to address specific drug metabolism-related issues in
drug discovery. Due to the risk of^3 Hexchange with water and loss of the
tritium label via biotransformation reactions, radiolabeled drug metabolism
and disposition studies in support of drug development and registrations
mainly rely on^14 C-radiolabeled analogs even though their synthesis requires a
resource-intensive effort. These studies include: (1) comparativein vitrometa-
bolism; (2) absorption, distribution, metabolism and elimination (ADME)
studies in toxicological species (Fouda et al., 1997; Graf et al., 2005; Li et al.,
2006; Zhang et al., 2007b); (3) tissue distribution study in rats or other species
(Hazai et al., 1999; Magyar et al., 1998); (4) ADME study in humans (Zhang
et al., 2005, 2007b); (5) enzymatic studies to identify the enzymes involved in

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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