TY - JOUR T1 - Trazodone Is Metabolized to<em>m</em>-Chlorophenylpiperazine by CYP3A4 from Human Sources JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 572 LP - 575 VL - 26 IS - 6 AU - Susan Rotzinger AU - Jian Fang AU - Glen B. Baker Y1 - 1998/06/01 UR - http://dmd.aspetjournals.org/content/26/6/572.abstract N2 - The metabolism of the antidepressant drug trazodone to its active metabolite, m-chlorophenylpiperazine (mCPP), was studiedin vitro using human liver microsomal preparations and cDNA-expressed human cytochrome P450 (P450) enzymes. The kinetics of mCPP formation from trazodone were determined, and three in vitro experiments were performed to identify the major P450 enzyme involved. Trazodone (100 μM) was incubated with 16 different human liver microsomal preparations characterized for activities of 7 different P450 isoforms. The production of mCPP correlated significantly with activity of cytochrome P4503A4 (CYP3A4) only. Trazodone (100 μM) was then incubated with microsomes from cells expressing human CYP1A1, CYP1A2, CYP2C8, CYP2C9arg, CYP2C9cys, CYP2C19, CYP2D6, or CYP3A4. Only incubations with CYP3A4 resulted in mCPP formation. In the third experiment, the CYP3A4 inhibitor ketoconazole was found 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 CYP3A4, that CYP3A4 is a major isoform involved in the production of mCPP from trazodone, and that there is the possibility of drug-drug interactions with trazodone and other substrates, inducers and/or inhibitors of CYP3A4. The American Society for Pharmacology and Experimental Therapeutics ER -