Effect of antipsychotic drugs on human liver cytochrome P-450 (CYP) isoforms in vitro: preferential inhibition of CYP2D6.

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 IC(50) values (2.7 and 1.5 microM) that were comparable to that of quinidine (0.52 microM). The estimated K(i) values for CYP2D6-catalyzing dextrorphan formation were ranked in the following order: perphenazine (0.8 microM), thioridazine (1.4 microM), chlorpromazine (6.4 microM), haloperidol (7.2 microM), fluphenazine (9.4 microM), risperidone (21.9 microM), clozapine (39.0 microM), and cis-thiothixene (65.0 microM). No remarkable inhibition of other CYP isoforms was observed except for moderate inhibition of CYP1A2-catalyzed phenacetin O-deethylation by fluphenazine (K(i) = 40.2 microM) and perphenazine (K(i) = 65.1). The estimated K(i) values for the inhibition of CYP2C9, 2C19, and 3A were >300 microM 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.