title: Intracellular and plasma pharmacokinetics of nevirapine in human immunodeficiency virus-infected individuals.
abstract: 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.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Liverpool, UK. lisaa@liv.ac.uk
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Almond
authors.forename: Damitha
authors.initials: D
authors.lastname: Edirisinghe
authors.forename: Mark
authors.initials: M
authors.lastname: Dalton
authors.forename: Alec
authors.initials: A
authors.lastname: Bonington
authors.forename: David J
authors.initials: DJ
authors.lastname: Back
authors.forename: Saye H
authors.initials: SH
authors.lastname: Khoo
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000328:Adult; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D005260:Female; D015658:HIV Infections; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000097:blood / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine