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Vol. 30, Issue 12, 1311-1319, December 2002
Office of Clinical Pharmacology and Biopharmaceutics, Center for
Drug Evaluation and Research, United States Food and Drug
Administration, Rockville, Maryland
Pharmaceutical industry investigators routinely evaluate the
potential for a new drug to modify cytochrome P450 (P450)
activities by determining the effect of the drug on in vitro probe
reactions that represent activity of specific P450 enzymes. The in
vitro findings obtained with one probe substrate are usually
extrapolated to the compound's potential to affect all substrates of
the same enzyme. Due to this practice, it is important to use the right probe substrate and to conduct the experiment under optimal conditions. Surveys conducted by reviewers in CDER indicated that the most common
in vitro probe reactions used by industry investigators include the
following: phenacetin O-deethylation for CYP1A2,
coumarin 7-hydroxylation for CYP2A6, 7-ethoxy-4-trifluoromethyl
coumarin O-dealkylation for CYP2B6, tolbutamide
4'-hydroxylation for CYP2C9, S-mephenytoin
4-hydroxylation for CYP2C19, bufuralol 1'-hydroxylation for CYP2D6,
chlorzoxazone 6-hydroxylation for CYP2E1, and testosterone 6
-hydroxylation for CYP3A4. We reviewed the validation information in the literature on these reactions and other frequently used reactions, including caffeine N3-demethylation for
CYP1A2, S-mephenytoin N-demethylation for
CYP2B6, S-warfarin 7'-hydroxylation for CYP2C9, dextromethorphan O-demethylation for CYP2D6, and
midazolam 1'-hydroxylation for CYP3A4. The available information
indicates that we need to continue the search for better probe
substrates for some enzymes. For CYP3A4-based drug interactions it may
be necessary to evaluate two or more probe substrates. In many cases,
the probe reaction represents a particular enzyme activity only under
specific experimental conditions. Investigators must consider
appropriateness of probe substrates and experimental conditions when
conducting in vitro drug interaction studies and when extrapolating the
results to in vivo situations.
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