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Vol. 26, Issue 3, 207-215, March 1998
Department of Pharmaceutics, University of Washington
There is a need for methodology to predict clinically
significant drug-drug interactions so that clinical studies can be
directed toward interactions which are likely to be clinically
relevant. To this end, we evaluated selective assays for the seven
drug-metabolizing cytochrome P450 (P450) isozymes 1A2 (caffeine
N3-demethylation), 2A6 (coumarin 7-hydroxylation), 2C9
(tolbutamide hydroxylation), 2C19 (S-mephenytoin
4-hydroxylation), 2D6 (dextromethorphan O-demethylation), 2E1 (chlorzoxazone 6-hydroxylation), and 3A4/5 (dextromethorphan N-demethylation). Using initial rate conditions, we
determined the Km and
Vmax values of each reaction in human
liver microsomes from three individuals. Because organic solvents
(usually methanol) are frequently used as solubilization aids for
drugs/inhibitors, we also screened several solvents for inhibitory
activity. Methanol was the least inhibitory toward P450s 2A6, 2D6, and
3A4, dimethylformamide was the least inhibitory toward P450s 1A2 and
2C9, and acetonitrile was the least inhibitory toward P450s 2C19 and
2E1. Using substrate concentrations close to the determined
Km and an appropriate solvent (where
necessary), we used the selective inhibitors furafylline (1A2),
8-methoxypsoralen (2A6), sulfaphenazole (2C9),
S-mephenytoin (2C19), quinidine (2D6),
diethyldithiocarbamate (2E1), and troleandomycin (3A4) to assess the
limitations of each probe assay as an indicator of the P450 isoform in
question. Our results were consistent with these inhibitors and probes,
being selective tools for studying P450 drug metabolism.
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