title: Inhibition of Efavirenz Metabolism by Sertraline and Nortriptyline and Their Effect on Efavirenz Plasma Concentrations.
abstract: Between 22 and 45% of HIV-positive subjects are likely to report symptoms of depression. Considering this background, a potential pharmacokinetic interaction between the nonnucleoside reverse transcriptase inhibitor efavirenz (EFV) and two antidepressants, sertraline (SRT) and nortriptyline (NT), was studied. Rats were administered EFV alone or together with the antidepressants, and changes in the plasma levels and pharmacokinetic parameters of EFV were analyzed. Additional in vitro experiments with rat and human hepatic microsomes were carried out to evaluate the inhibitory effect of SRT and NT on EFV metabolism by determining the formation rate of the major EFV metabolite (8-OH-EFV). In vivo studies showed similar increases in the plasma levels of EFV when it was coadministered with SRT or NT. However, the studies using rat hepatic microsomes showed a more potent inhibitory effect of NT than of SRT on the metabolism of EFV, with values for the 50% inhibition constant (IC50) and inhibitory constant (Ki) for NT about 9-fold lower than those for SRT. An equation was deduced that explains the similar in vivo effects of SRT and NT in spite of the different in vitro performance data. Using human hepatic microsomes, the strongest inhibitory effect was observed with SRT. In summary, pharmacokinetic interactions between EFV, SRT, and NT, associated with the inhibition of hepatic metabolism of EFV, have been detected in rats. Both antidepressants also inhibit EFV metabolism in human hepatic microsomes, but additional in vivo studies in humans are required to evaluate the clinical implication of this interaction.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Valencia, Valencia, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Melis
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Valencia, Valencia, Spain.
authors.forename: Iris
authors.initials: I
authors.lastname: Usach
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Valencia, Valencia, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Gandía
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Valencia, Valencia, Spain jose.e.peris@uv.es.
authors.forename: José-Esteban
authors.initials: JE
authors.lastname: Peris
mesh_terms: D000480:Alkynes; D000818:Animals; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics; D000928:Antidepressive Agents / Q000494:pharmacology*; D048588:Benzoxazines / Q000097:blood* / Q000493:pharmacokinetics*; D003521:Cyclopropanes; D004347:Drug Interactions; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009661:Nortriptyline / Q000494:pharmacology*; D017208:Rats, Wistar; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000493:pharmacokinetics; D020280:Sertraline / Q000494:pharmacology*
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D000928:Antidepressive Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D009661:Nortriptyline; C098320:efavirenz; D020280:Sertraline