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In vitro assessment of competitive and time-dependent inhibition of the nevirapine metabolism by nortriptyline in rats
- Source :
- Biochemical Pharmacology. 154:1-9
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1) widely used as a component of High Active Antiretroviral Therapy (HAART) since it is inexpensive, readily absorbed after oral administration and non-teratogenic. In the present work, the mechanism of a previously described pharmacokinetic interaction between NVP and the antidepressant drug nortriptyline (NT) was studied using rat hepatic microsomes. The obtained results showed a competitive inhibition of the NVP metabolism by NT. The three main NVP metabolites (2-OH-NVP, 3-OH-NVP and 12-OH-NVP) where competitively inhibited with similar inhibitory constant values (Ki = 4.01, 3.97 and 4.40 μM, respectively). Time-dependent inhibition of the NVP metabolism was also detected, with a 2.5-fold reduction in the IC50 values of NT for 2-, 3-, and 12-OH-NVP formation when NT was preincubated with the microsomal suspension in the presence of an NADPH-generating system. A concentration-dependent inhibition of the formation of NVP metabolites by the main NT metabolite (10-OH-NT) was also observed, however, the inhibitory potency of 10-OH-NT was much lower than that of the parent drug. The apparent hepatic intrinsic clearance of NVP determined in these in vitro experiments was used to predict the in vivo clearance of NVP using the “well-stirred” and the “parallel-tube” models, resulting in values close to those previously observed in vivo clearance. Finally, a good prediction of the increase in the plasma concentrations of NVP when co-administered with NT was obtained employing the inhibitory constant of NT determined in vitro and the estimated plasma concentration of NT entering the liver.
- Subjects :
- Male
0301 basic medicine
Time Factors
Metabolite
030106 microbiology
Nortriptyline
Antidepressive Agents, Tricyclic
Pharmacology
Binding, Competitive
030226 pharmacology & pharmacy
Biochemistry
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Non-competitive inhibition
immune system diseases
Oral administration
In vivo
medicine
Animals
Nevirapine
Rats, Wistar
Reverse-transcriptase inhibitor
Chemistry
virus diseases
Rats
Microsomes, Liver
Microsome
Reverse Transcriptase Inhibitors
Drug metabolism
medicine.drug
Subjects
Details
- ISSN :
- 00062952
- Volume :
- 154
- Database :
- OpenAIRE
- Journal :
- Biochemical Pharmacology
- Accession number :
- edsair.doi.dedup.....db80939e26c01ff88ca8371491865f91