title: Pharmacokinetic interaction between nevirapine and nortriptyline in rats: inhibition of nevirapine metabolism by nortriptyline.
abstract: One of the most frequent comorbidities of HIV infection is depression, with a lifetime prevalence of 22 to 45%. Therefore, it was decided to study a potential pharmacokinetic interaction between the nonnucleoside reverse transcriptase inhibitor nevirapine (NVP) and the tricyclic antidepressant nortriptyline (NT). NVP and NT were administered to rats either orally, intraduodenally, or intravenously, and the changes in plasma levels and pharmacokinetic parameters were analyzed. Experiments with rat and human hepatic microsomes were carried out to evaluate the inhibitory effects of NT on NVP metabolism. NVP plasma concentrations were significantly higher when this drug was coadministered with NT. The maximum plasma concentrations of NVP were increased 2 to 5 times and the total plasma clearance was decreased 7-fold in the presence of NT. However, statistically significant differences in the pharmacokinetic parameters of NT in the absence and presence of NVP were not found. In vitro studies with rat and human hepatic microsomes confirmed the inhibition of NVP hepatic metabolism by NT in a concentration-dependent way, with the inhibition being more intense in the case of rat microsomes. In conclusion, a pharmacokinetic interaction between NVP and NT was detected. This interaction was a consequence of the inhibition of hepatic metabolism of NVP by NT. In vivo human studies are required to evaluate the effects of this interaction on the pharmacokinetics of NVP before it can be taken into account for patients receiving NVP.
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: 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: 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: D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001711:Biotransformation; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D019829:Nevirapine / Q000037:antagonists & inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D009661:Nortriptyline / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D000929:Antidepressive Agents, Tricyclic; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; D009661:Nortriptyline