In Vitro Metabolism of Trazodone by CYP3A: Inhibition by Ketoconazole and Human Immunodeficiency Viral Protease Inhibitors Alysa Zalma, Lisa L. von Moltke, Brian W. Granda, Jerold S. Harmatz, Richard I. Shader, and David J. Greenblatt Background: Pharmacologic treatment of emotional dis- orders in HIV-infected patients can be more easily opti- mized by understanding of potential interactions of psy- chotropic drugs with medications used to treat HIV infection and its sequelae. Methods: Biotransformation of the antidepressant traz- odone to its principal metabolite, meta-chlorophe- nylpiperazine (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) K m value of 163 ( 21) mol/L. Ketoconazole, a relatively specific CYP3A inhib- itor, impaired mCPP formation consistent with a compet- itive mechanism, having an inhibition constant (K i ) of 0.12 ( 0.01) mol/L. Among heterologously expressed human cytochromes, only CYP3A4 mediated formation of mCPP from trazodone; the K m was 180 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 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 ketoconazole, ritonavir and indinavir, and indicates the likelihood of pharmacokinetic interactions in vivo. Biol Psychiatry 2000;47:655– 661 © 2000 Society of Biological Psychiatry Key Words: Trazodone, m-chlorophenylpiperazine, CYP3A, ketoconazole, viral protease inhibitors Introduction U se of the human immunodeficiency viral protease inhibitors (HIVPIs) in combination with other anti-HIV drugs has decreased morbidity and mortality in patients with HIV infection (Barry et al 1998; Carpenter et al 1998; Flexner 1998; Moyle et al 1998). The HIVPIs are also responsible for a number of drug interactions due to their ability to induce and/or inhibit drug metabolism in humans (Barry et al 1997; Hsu et al 1998). Because emotional disorders are commonly en- countered in patients with HIV infection, interactions of anti-HIV medications with psychotropic drugs may warrant clinical concern. Trazodone is an antidepressant available since the early 1980s that has a pharmacologic profile differing from the older heterocyclic antidepressants, the mono- amine oxide inhibitors, and the selective serotonin reuptake inhibitors (Brogden et al 1981; Georgotas et al 1982). Trazodone is currently used for a variety of disorders, including depression, anxiety, neuropathic pain, and sexual dysfunction. Trazodone also is com- monly used to treat insomnia. Since HIV patients suffer from a number of comorbid conditions such as these (Bluestine and Lesko 1994; Darko et al 1992; Grant 1990; Snyder et al 1990; van Gorp and Buckingham 1998), trazodone is often used as a psychotropic med- ication in individuals with HIV infection. The present study utilized an in vitro model based on human liver microsomal preparations and heterologously expressed human cytochromes to evaluate the enzyme kinetic characteristics of biotransformation of trazodone to its major metabolite m-chlorophenylpiperazine (mCPP), which is anxiogenic. The extent to which mCPP formation accounts for net metabolic clearance of trazodone has not been established, since other human metabolites of traz- odone have been described (Baiocchi and Frigerio 1974; Jauch et al 1976). The study also evaluated the relative capacity of the azole antifungal agent, ketoconazole, and of HIVPIs, to inhibit metabolism of trazodone. From the Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and the Division of Clinical Pharmacology, New England Medical Center Hospitals, Boston, Massachusetts. Address reprint requests to David J. Greenblatt, M.D., Department of Pharmacol- ogy and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111. Received March 8, 1999; revised June 22, 1999; accepted June 23, 1999. © 2000 Society of Biological Psychiatry 0006-3223/00/$20.00 PII S0006-3223(99)00176-6