5 Metabolism-Mediated Drug–Drug Interactions
HONGJIANZHANG,MICHAELW. SINZ,ANDA. DAVIDRODRIGUES
5.1 INTRODUCTION
Serious drug–drug interactions (DDIs) are major liabilities for any new drug
entering the pharmaceutical marketplace. In recognition of the importance of
such drug interactions, pharmaceutical companies employ rapid in vitro
screening methods in drug discovery to eliminate problematic compounds, in
addition to conducting more detailed studies in drug development to fully
characterize and assess the potential liability. Eventually, the drug interaction
(or lack thereof) is fully evaluated in patients or volunteers during early clinical
trails. Although drug interactions can lead to changes in the pharmacologic
(pharmacodynamic) profile of drugs, the present discussion will focus on
metabolic drug interactions leading to altered pharmacokinetics. Classical
metabolic drug interactions involve inhibition or induction of drug-metabolizing
enzyme activities. This is especially critical when a given drug is predominately
cleared by a polymorphically expressed drug-metabolizing enzyme, or by a single
enzyme susceptible to inhibition or induction.
In the proceeding paragraphs, illustrations of metabolic drug interactions
will be described. Throughout, drugs will be described as either ‘‘victims’’ or
‘‘perpetrators’’ of drug interactions. A perpetrator is a drug causing a change
in enzyme activity (increase or decrease) and a victim is a drug affected by
altered metabolism/pharmacokinetics (either through increased or through
decreased metabolism). Although most of the examples described herein focus
Drug Metabolism in Drug Design and Development, Edited by Donglu Zhang, Mingshe Zhu
and W. Griffith Humphreys
Copyright#2008 John Wiley & Sons, Inc.
113