17 Testing Drug Candidates for CYP3A4 Induction
GANGLUO,LIANG-SHANGGAN,ANDTHOMASM. GUENTHNER
17.1 INTRODUCTION
The primary objective of preclinical drug evaluation is characterization of the
direct pharmacological and toxicological activities of the candidate molecules.
However, a major concern of preclinical drug development is also the
prediction of eventual interactions between the drug candidate and other drugs
or xenobiotics that may be simultaneously present. Drug–drug interactions are
normally understood to occur when the effects of two or more drugs are
qualitatively or quantitatively different from the simple sum of the effects
observed when the same doses of the drugs are present separately. Drug–drug
interactions involving drug metabolism are certainly among the most
prevalently encountered therapeutically, and elucidation of the potential of
candidate drug molecules to either inhibit or induce drug metabolism is among
the most important objectives of the drug development process.
A prevalent type of metabolism-dependent drug–drug interaction occurs
when one drug increases the clearance of a second, by increasing its rate of
metabolism, usually through a mechanism of action known as enzyme
induction. Although this type of drug–drug interaction is probably less
common than that involving inhibition of drug metabolism, and is less likely to
jeopardize patient safety, it nevertheless can produce significant clinical
consequences, manifested primarily as lower blood levels, decreased half-life,
and possible therapeutic failure. A well-documented historical example of this
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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