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Vol. 28, Issue 2, 125-130, February 2000
Department of Drug Metabolism, Merck Research Laboratories, West
Point, Pennsylvania.
The inhibitory effects of six commonly used calcium channel
blockers on three major cytochrome P-450 activities were examined and
characterized in human liver microsomes. All six compounds reversibly
inhibited CYP2D6 (bufuralol 1'-hydroxylation) and CYP2C9 (tolbutamide
methyl hydroxylation) activities. The IC50 values for the
inhibition of CYP2D6 and CYP2C9 for nicardipine were 3 to 9 µM,
whereas those for all others ranged from 14 to >150 µM. Except for
nifedipine, all calcium channel blockers showed increased inhibitory potency toward CYP3A activities (testosterone
6
-hydroxylation and midazolam 1'-hydroxylation) after 30-min
preincubation with NADPH. IC50 values for the inhibition of
testosterone 6-hydroxylase obtained in the NADPH-preincubation
experiment for nicardipine (1 µM), verapamil (2 µM), and diltiazem
(5 µM) were within 10-fold, whereas those for amlodipine (5 µM) and
felodipine (13 µM) were >200-fold of their respective plasma
concentrations reported after therapeutic doses. Similar results also
were obtained based on midazolam 1'-hydroxylase activity. Unlike the
observations with mibefradil, a potent irreversible inhibitor of CYP3A,
the NADPH-dependent inhibition of CYP3A activity by nicardipine
and verapamil was completely reversible on dialysis, whereas that by
diltiazem was partially restored (80%). Additional experiments
revealed that nicardipine, verapamil, and diltiazem formed cytochrome
P-450-iron (II)-metabolite complex in both human liver
microsomes and recombinant CYP3A4. Nicardipine yielded a higher extent
of complex formation (~30% at 100 µM), and was a much
faster-acting inhibitor (maximal inhibition rate constant ~2
min
1) as compared with verapamil and diltiazem. These
present findings that the CYP3A inhibition caused by nicardipine,
verapamil, and diltiazem is, at least in part, quasi-irreversible
provide a rational basis for pharmacokinetically significant
interactions reported when they were coadministered with agents that
are cleared primarily by CYP3A-mediated pathways.
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