TRAZODONE IS METABOLIZED TO M-CHLOROPHENYLPIPERAZINE BY CYP3A4 FROM HUMAN SOURCES

The metabolism of the antidepressant drug trazodone to its active meta bolite, m-chlorophenylpiperazine (mCPP), was studied in vitro using hu man liver microsomal preparations and cDNA-expressed human cytochrome P450 (P450) enzymes. The kinetics of mCPP formation from trazodone wer e determined, and three in vitro experiments were performed to identif y the major P450 enzyme involved, Trazodone (100 mu M) was incubated w ith 16 different human liver microsomal preparations characterized for activities of 7 different P450 isoforms. The production of mCPP corre lated significantly with activity of cytochrome P4503A4 (CYP3A4) only. Trazodone (100 mu M) was then incubated with microsomes from cells ex pressing human CYP1A1, CYP1A2, CYP2C8, CYP2C9arg, CYP2C9cys, CYP2C19, CYP2D6, or CYP3A4. Only incubations with CYP3A4 resulted in mCPP forma tion. In the third experiment, the CYP3A4 inhibitor ketoconazole was f ound to inhibit mCPP formation concentration dependently in both human liver microsomes and in microsomes from cells expressing human CYP3A4 . The present results indicate that trazodone is a substrate for CYP3A 4, that CYP3A4 is a major isoform involved in the production of mCPP f rom trazodone, and that there is the possibility of drug-drug interact ions with trazodone and other substrates, inducers and/or inhibitors o f CYP3A4.