Identification of the human cytochrome P450 isoforms mediating in vitro N-dealkylation of perphenazine

摘要: Aims To identify the human cytochrome P450 (CYP) isoforms mediating N-dealkylation of antipsychotic drug perphenazine in vitro and estimate relative contributions CYP involved. Methods cDNA-expressed were used to that are able mediate perphenazine, which is considered a major metabolic pathway for drug. Using liver microsomal preparations (HLM), inhibition studies carried out establish involved reaction. Results 1A2, 3A4, 2C8, 2C9, 2C18, 2C19 2D6 perphenazine. Reaction velocities their abundance HLM suggested CYP1A2, most important contributors N-dealkylation. Apparent Km values CYP1A2 CYP2D6 range 1–2 µm, CYP2C19 CYP3A4 14 µm 7.9 µm, respectively. Ketoconazole mediated by mixed indicated accounted about 40% at therapeutically relevant concentrations.The contribution amounted 20–25% each as measured percentage obtained addition furafylline, fluvoxamine or quinidine, HLM-mediated 57% total amount substrate consumed during incubation. Conclusions The present study suggests 2CD6 primarily relatively modest role variance with vivo studies, indicate greater this isoform. Alternative pathways, corresponding 43% metabolism drug, may depend more strongly on CYP2D6.