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 interac tions of psychotropic drugs with medications used to treat HIV infection an d 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 cytoc hromes. Interactions of trazodone with the azole antifungal agent, ketocona zole, and with human immunodeficiency virus protease inhibitors (HIVPIs) we re studied in the same system. Results: Formation of mCPP from trazodone in liver microsomes has a mean (/- SE) K-m value of 163 (+/- 21) mu mol/L. Among heterologously expressed h uman cytochromes, only CYP3A4 mediated formation of mCPP from trazodone; th e K-m was 180 mu mol/L, consistent with the value in microsomes. The HIVPI ritonavir was a potent inhibitor of mCPP formation in liver microsomes (K-i = 0.14 +/- 0.04 mu mol/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 ketocona zole, ritonavir and indinavir, and indicates the likelihood of pharmacokine tic interactions in vivo. (C) 2000 Society of Biological Psychiatry.