In vitro metabolism of trazodone by CYP3A: inhibition by ketoconazole and human immunodeficiency viral protease inhibitors

Background: Pharmacologic treatment of emotional disorders in HIV-infected patients can be more easily optimized by understanding of potential interactions of psychotropic drugs with medications used to treat HIV infection and its sequelae. Methods: Biotransformation of the antidepressant trazodone to its principal metabolite, meta-chlorophenylpiperazine (mCPP), was studied in vitro using human liver microsomes and heterologously expressed individual human cytochromes. Interactions of trazodone with the azole antifungal agent, ketoconazole, and with human immunodeficiency virus protease inhibitors (HIVPIs) were studied in the same system. Results: Formation of mCPP from trazodone in liver microsomes had a mean (± SE) Km value of 163 (± 21) μmol/L. Ketoconazole, a relatively specific CYP3A inhibitor, impaired mCPP formation consistent with a competitive mechanism, having an inhibition constant (Ki) of 0.12 (± 0.01) μmol/L. Among heterologously expressed human cytochromes, only CYP3A4 mediated formation of mCPP from trazodone; the Km was 180 μmol/L, consistent with the value in microsomes. The HIVPI ritonavir was a potent inhibitor of mCPP formation in liver microsomes (Ki = 0.14 ± 0.04 μmol/L). The HIVPI indinavir was also a strong inhibitor, whereas saquinavir and nelfinavir were weaker inhibitors. Conclusions: CYP3A-mediated clearance of trazodone is inhibited by ketoconazole, ritonavir and indinavir, and indicates the likelihood of pharmacokinetic interactions in vivo.