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Intracellular and plasma pharmacokinetics of nevirapine in human immunodeficiency virus‐infected individuals
Author(s) -
Almond Lisa M.,
Edirisinghe Damitha,
Dalton Mark,
Bonington Alec,
Back David J.,
Khoo Saye H.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.04.004
Subject(s) - nevirapine , pharmacokinetics , virology , human immunodeficiency virus (hiv) , intracellular , medicine , biology , pharmacology , antiretroviral therapy , viral load , genetics
Background and Objective Plasma concentrations of nevirapine have been linked to human immunodeficiency virus (HIV) treatment outcome. However, because the site of action of nevirapine is within HIV‐infected cells, intracellular concentrations may better relate to antiviral exposure. Investigation of factors that alter the intracellular pharmacokinetics of nevirapine may also aid in our understanding of therapeutic failure. Our objective was to determine intracellular (or cell‐associated) nevirapine concentrations over the full dosing interval and to relate protein binding and P‐glycoprotein (P‐gp) expression to intracellular exposure. Methods Plasma and peripheral blood mononuclear cells were isolated from blood samples taken from 10 HIV‐infected patients at 0, 2, 4, 8, and 12 hours after dosing. Intracellular and plasma (total and unbound) concentrations were determined by liquid chromatography‐tandem mass spectrometry, and the ratios of intracellular to total plasma exposure (area under the concentration‐time curves) were calculated. P‐gp expression was measured by flow cytometry. Results The median intracellular accumulation ratio was 0.005 (range, 0.001–0.054) and remained unchanged over the dosing interval. There was an association between higher plasma concentrations and lower cellular concentrations of nevirapine (total r 2 = 0.62, P = .007). There was no relationship between percent unbound nevirapine and intracellular nevirapine. There was a correlation between higher plasma nevirapine exposure and higher P‐gp expression ( r 2 = 0.77, P = .03), whereas intracellular nevirapine exposure decreased with higher P‐gp expression ( r 2 = 0.62, P = .01). Conclusions The intracellular accumulation of nevirapine was low, did not change over the dosing interval, and was not related to protein binding. In this small study, cells with higher P‐gp expression had lower cellular concentrations of nevirapine. Further studies are required to explore the influx and efflux transporter profile of this drug. Clinical Pharmacology & Therapeutics (2005) 78 , 132–142; doi: 10.1016/j.clpt.2005.04.004