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

Aims To identify the human cytochrome P450 (CYP) isoforms mediating the N‐dealkylation of the antipsychotic drug perphenazine in vitro and estimate the relative contributions of the CYP isoforms involved.

Methods cDNA‐expressed CYP isoforms were used to identify the isoforms that are able to mediate the N‐dealkylation of perphenazine, which is considered a major metabolic pathway for the drug. Using human liver microsomal preparations (HLM), inhibition studies were carried out to establish the relative contributions of the CYP isoforms involved in the N‐dealkylation reaction.

Results CYP isoforms 1A2, 3A4, 2C8, 2C9, 2C18, 2C19 and 2D6 were able to mediate the N‐dealkylation of perphenazine. Reaction velocities and their relative abundance in HLM suggested that CYP1A2, 3A4, 2C19 and 2D6 were the most important contributors to N‐dealkylation. Apparent K_m values of CYP1A2 and CYP2D6 were in the range 1–2 µm, and K_m values of CYP2C19 and CYP3A4 were 14 µm and 7.9 µm, respectively. Ketoconazole inhibition of N‐dealkylation mediated by a mixed HLM indicated that CYP3A4 accounted for about 40% of perphenazine N‐dealkylation at therapeutically relevant concentrations.The contribution of the CYP isoforms 1A2, 2C19 and 2D6 amounted to 20–25% each as measured by the percentage inhibition obtained by addition of furafylline, fluvoxamine or quinidine, respectively. HLM‐mediated N‐dealkylation of perphenazine accounted for 57% of the total amount of substrate consumed during incubation.

Conclusions The present in vitro study suggests that CYP isoforms 1A2, 3A4, 2C19 and 2CD6 are primarily involved in the N‐dealkylation of perphenazine. The relatively modest role of CYP2D6 is at variance with in vivo studies, which indicate a greater contribution of this isoform. Alternative metabolic pathways, corresponding to 43% of the HLM‐mediated metabolism of the drug, may depend more strongly on CYP2D6.

DOI: 10.1046/j.1365-2125.2000.00298.x

View this article

• Full article (html)
• Enhanced article (html)
• PDF
• References