Metabolism of Quetiapine by CYP3A4 and CYP3A5 in Presence or Absence of Cytochrome B5

The antipsychotic drug quetiapine is extensively metabolized by CYP3A4, but little is known about the possible influence of the polymorphic enzyme CYP3A5. This in vitro study investigated the relative importance of CYP3A4 and CYP3A5 in the metabolism of quetiapine and compared the metabolic pattern by the two enzymes, in the presence or absence of cytochrome b5. Intrinsic clearance (CLint) of quetiapine was determined by the substrate depletion approach in CYP3A4 and CYP3A5 insect cell microsomes with or without coexpressed cytochrome b5. Formation of the metabolites quetiapine sulfoxide, N-desalkylquetiapine, O-desalkylquetiapine, and 7-hydroxyquetiapine by CYP3A4 and CYP3A5 were compared in the different microsomal preparations. CLint of quetiapine by CYP3A5 was less than 35% relative to CYP3A4. CLint was higher (3-fold) in CYP3A4 microsomes without cytochrome b5 compared with CYP3A4 microsomes with coexpressed cytochrome b5, whereas in CYP3A5 microsomes CLint was similar for both microsomal preparations. Metabolism of quetiapine by CYP3A5 revealed a different metabolic pattern compared with CYP3A4. The results indicated that O-desalkylquetiapine constituted a higher proportion of the formed metabolites by CYP3A5 compared with CYP3A4. In conclusion, the present study indicates that CYP3A5 is of minor importance for the overall metabolism of quetiapine, regardless of the presence of cytochrome b5. However, a different metabolic pattern by CYP3A5 compared with CYP3A4 could possibly result in different pharmacological and/or toxicological effects of quetiapine in patients expressing CYP3A5.