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) K(m) value of 163 (+/- 21) micromol/L. Ketoconazole, a relatively specific CYP3A inhibitor, impaired mCPP formation consistent with a competitive mechanism, having an inhibition constant (K(i)) of 0.12 (+/- 0.01) micromol/L. Among heterologously expressed human cytochromes, only CYP3A4 mediated formation of mCPP from trazodone; the K(m) was 180 micromol/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 micromol/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.
Zalma
A
A
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
von Moltke
L L
LL
Granda
B W
BW
Harmatz
J S
JS
Shader
R I
RI
Greenblatt
D J
DJ
D018687:Antidepressive Agents, Second-Generation / Q000378:metabolism; D000935:Antifungal Agents / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D017320:HIV Protease Inhibitors / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D019469:Indinavir / Q000378:metabolism; D007654:Ketoconazole / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D019888:Nelfinavir / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism; D019438:Ritonavir / Q000378:metabolism; D019258:Saquinavir / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics; D014196:Trazodone / Q000378:metabolism* / Q000493:pharmacokinetics
D018687:Antidepressive Agents, Second-Generation; D000935:Antifungal Agents; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D017320:HIV Protease Inhibitors; D019469:Indinavir; D007654:Ketoconazole; D019888:Nelfinavir; D010089:Oxidoreductases, N-Demethylating; D010879:Piperazines; D019438:Ritonavir; D019258:Saquinavir; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D014196:Trazodone; C015068:1-(3-chlorophenyl)piperazine