HUMAN CYP2D6 AND METABOLISM OF M-CHLOROPHENYLPIPERAZINE

Background: Metabolic drug-drug interactions cart occur between drugs that are substrates or inhibitors of the same cytochrome P450 (CYP) is oenzymes, but can be prevented by knowing which isoenzymes are primari ly responsible for a drug's metabolism. m-Chlorophenylpiperazine (mCPP ) is a psychopharmacologically active metabolite of four different psy chiatric drugs. The present experiments were designed to identify the CYP isoenzymes involved in the metabolism of mCPP to its main metaboli te p-hydroxy-mCPP (OH-mCPP). Methods: The rate of production of OH-mCP P from mCPP was correlated with isoform activities in a panel of human liver microsomes, was assessed using a panel of individual complement ary DNA-expressed human CYP isoenzymes, and was investigated in the pr esence of a specific inhibitor of CYP2D6. Results: OH-mCPP production correlated significantly with CYP2D6 activity in human liver microsome s. Furthermore, incubations with microsomes from cells expressing CYP2 D6 resulted in OH-mCPP formation, whereas no mCPP was formed from incu bations with microsomes from cells expressing other individual isoform s. Finally, when the specific CYP2D6 inhibitor quinidine It as preincu bated with either human liver microsomes or cells expressing human CYP 2D6, there was a concentration-dependent decrease in the production of OH-mCPP, Conclusions: These results confirm that CYP2D6 is the isofro m responsible for the p-hydroxylation of mCPP, and indicate that cauti on should be exercised in coprescribing inhibitors or substrates of CY P2D6 with drugs that have mCPP as a metabolite. (C) 1998 Society of Bi ological Psychiatry.