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Vol. 27, Issue 9, 1078-1084, September 1999
Division of Clinical Pharmacology, Departments of Medicine
and Pharmacology, Georgetown University Medical Center, Washington
The ability of antipsychotic drugs to inhibit the catalytic
activity of five cytochrome P-450 (CYP) isoforms was compared using in
vitro human liver microsomal preparations to evaluate the relative
potential of these drugs to inhibit drug metabolism. The apparent
kinetic parameters for enzyme inhibition were determined by nonlinear
regression analysis of the data. All antipsychotic drugs tested
competitively inhibited dextromethorphan
O-demethylation, a selective marker for CYP2D6, in a
concentration-dependent manner. Thioridazine and perphenazine were the
most potent, with IC50 values (2.7 and 1.5 µM) that were
comparable to that of quinidine (0.52 µM). The estimated
Ki values for CYP2D6-catalyzing dextrorphan formation were ranked in the following order: perphenazine (0.8 µM),
thioridazine (1.4 µM), chlorpromazine (6.4 µM), haloperidol (7.2 µM), fluphenazine (9.4 µM), risperidone (21.9 µM), clozapine (39.0 µM), and cis-thiothixene (65.0 µM). No
remarkable inhibition of other CYP isoforms was observed except for
moderate inhibition of CYP1A2-catalyzed phenacetin
O-deethylation by fluphenazine (Ki = 40.2 µM) and perphenazine
(Ki = 65.1). The estimated
Ki values for the inhibition of CYP2C9,
2C19, and 3A were >300 µM in almost all antipsychotics tested. These
results suggest that antipsychotic drugs exhibit a striking selectivity
for CYP2D6 compared with other CYP isoforms. This may reflect a
remarkable commonality of structure between the therapeutic targets for
these drugs, the transporters, and metabolic enzymes that distribute and eliminate them. Clinically, coadministration of these medicines with drugs that are primarily metabolized by CYP2D6 may result in
significant drug interactions.
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