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.

Inhibition of Efavirenz Metabolism by Sertraline and Nortriptyline and Their Effect on Efavirenz Plasma Concentrations

“…In order to check if equation 2 could be used to explain the in vivo results, an additional group of rats were intraduodenally dosed with 5 mg of SRT, and the following pharmacokinetic parameters were obtained: C max of 0.93 M and AUC inf of 522 M · min. With regard to NT, previously published data (41) were used (C max of 0.41 M and AUC inf of 57 M · min). Using these C max values to replace [I] in equation 2, the predicted AUC inf ratios were clearly lower than those observed in vivo: 1.01 versus 1.32 (SRT) and 1.05 versus 1.41 (NT).…”

“…(i) EFV metabolism and its inhibition by SRT and NT in rat hepatic microsomes. Wistar rat livers were processed as previously described (41) to obtain hepatic microsomes that were used for the study of the EFV metabolism. The rate of 8-OH EFV formation by hepatic microsomes was determined using different concentrations of EFV and glass vials as follows: a given volume of EFV in methanol (10 g/ml) was evaporated, and hepatic microsomes (equivalents to 0.1 mg of protein) were added to the residue together with 5 l of a solution of glucose-6-phosphate in water (20 mg/ml), 5 l of a solution of ␤-NADP ϩ in water (20 mg/ml), 10 l of a solution of glucose-6-phosphate dehydrogenase in water (10 U/ml), and 5 l of a solution of MgCl 2 in water (13.4 mg/ml).…”

Drug–drug interactions and clinical considerations with co-administration of antiretrovirals and psychotropic drugs

“…Desipramine clearance was reduced 59% by ritonavir in 1 pharmacokinetic study; however, a large daily ritonavir dose of 1000 mg was used, 55 which is higher than doses in modern practice 16 . Nortryptiline, a weak inhibitor of CYP 2D6, 53 increased nevirapine Cmax over 2-fold in an in vitro model 56 ; however, these results have yet to be replicated in humans, and therefore the clinical significance is uncertain. Despite this, an advantage of TCAs is that therapeutic drug monitoring is possible, allowing for identification of supratherapeutic concentrations if an interaction is suspected.…”