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Sex-dependent metabolism of nevirapine in rats: impact on plasma levels, pharmacokinetics and interaction with nortriptyline.
- Source :
-
International journal of antimicrobial agents [Int J Antimicrob Agents] 2018 May; Vol. 51 (5), pp. 707-713. Date of Electronic Publication: 2018 Jan 05. - Publication Year :
- 2018
-
Abstract
- Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) widely used in the treatment of human immunodeficiency virus type 1 (HIV-1) and is the first-choice NNRTI during pregnancy. NVP shows a sex dimorphic profile in humans with sex differences in bioavailability, biotransformation and toxicity. In this study, sex differences in NVP metabolism and inhibition of NVP metabolism by the antidepressant nortriptyline (NT) were evaluated using rats as experimental animals. NVP was administered orally to male and female rats and sex differences in plasma levels and pharmacokinetic parameters were analysed. NVP plasma levels were higher in female compared with male rats, and pharmacokinetic parameters such as maximum plasma concentration (C <subscript>max</subscript> ), time to C <subscript>max</subscript> (T <subscript>max</subscript> ), half-life (t <subscript>1/2</subscript> ) and area under the plasma concentration-time curve from the time of dosing to the last measurable concentration (AUC <subscript>last</subscript> ) showed ca. 4-, 5-, 7- and 22-fold higher values in female rats. In vitro experiments carried out with hepatic microsomes confirmed slower NVP metabolism in female rats, with a maximum velocity (V <subscript>max</subscript> ) 2-fold lower than in male hepatic microsomes. The major metabolite in both sexes was 12-hydroxynevirapine (12-OH-NVP), with the V <subscript>max</subscript> for this metabolite being 15-fold lower in female compared with male rat hepatic microsomes. Inhibition of NVP metabolism by NT was similar in both sexes, with statistically non-significant differences in 50% inhibitory concentration (IC <subscript>50</subscript> ) values. In summary, NVP is metabolised more slowly in female compared with male rats, but the inhibitory effect of NT is similar in both sexes.<br /> (Copyright © 2018 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)
- Subjects :
- Animals
Antidepressive Agents, Tricyclic pharmacokinetics
Drug Interactions
Female
Male
Microsomes, Liver drug effects
Nevirapine blood
Rats, Wistar
Reverse Transcriptase Inhibitors blood
Reverse Transcriptase Inhibitors pharmacokinetics
Sex Factors
Nevirapine pharmacokinetics
Nortriptyline pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7913
- Volume :
- 51
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- International journal of antimicrobial agents
- Publication Type :
- Academic Journal
- Accession number :
- 29309900
- Full Text :
- https://doi.org/10.1016/j.ijantimicag.2017.12.026