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 fiv e cytochrome P-450 (CYP) isoforms was compared using in vitro human liver m icrosomal preparations to evaluate the relative potential of these drugs to inhibit drug metabolism. The apparent kinetic parameters for enzyme inhibi tion were determined by nonlinear regression analysis of the data. All anti psychotic drugs tested competitively inhibited dextromethorphan O-demethyla tion, a selective marker for CYP2D6, in a concentration-dependent manner. T hioridazine and perphenazine were the most potent, with IC50 values (2.7 an d 1.5 mu M) that were comparable to that of quinidine (0.52 mu M). The esti mated K-i values for CYP2D6-catalyzing dextrorphan formation were ranked in the following order: perphenazine (0.8 mu M), thioridazine (1.4 mu M), chl orpromazine (6.4 mu M), haloperidol (7.2 mu M), fluphenazine (9.4 mu M), ri speridone (21.9 mu M), clozapine (39.0 mu M), and cis-thiothixene (65.0 mu M) No remarkable inhibition of other CYP isoforms was observed except for m oderate inhibition of CYP1A2-catalyzed phenacetin O-deethylation by fluphen azine (K-i = 40.2 mu M) and perphenazine (K-i = 65.1). The estimated K-i va lues for the inhibition of CYP2C9, 2C19, and 3A were >300 mu M in almost al l antipsychotics tested. These results suggest that antipsychotic drugs exh ibit a striking selectivity for CYP2D6 compared with other CYP isoforms. Th is may reflect a remarkable commonality of structure between the therapeuti c targets for these drugs, the transporters, and metabolic enzymes that dis tribute and eliminate them. Clinically, coadministration of these medicines with drugs that are primarily metabolized by CYP2D6 may result in signific ant drug interactions.