P-glycoprotein, multidrug resistance-associated proteins and human organic anion transporting polypeptide influence the intracellular accumulation of atazanavir

Antivir Ther. 2009;14(7):965-74. doi: 10.3851/IMP1399.


Background: Drug efflux (for example, P-glycoprotein [P-gp], multidrug resistance-associated proteins [MRPs] and breast cancer resistance protein [BCRP]) and influx (for example, human organic anion transporting polypeptide [hOCTP] or human organic anion transporting polypeptide [hOATP]) transporters alter the cellular concentrations of some HIV protease inhibitors (HPIs). Here, we studied the lipophilicity and uptake of [(3)H]-atazanavir (ATV) in CEM (parental), CEM(VBL) (P-gp-overexpressing), CEM(E1000) (MRP1-overexpressing) and peripheral blood mononuclear cells (PBMCs), and evaluate the effects of modulators of drug transporters on uptake.

Methods: Lipophilicity was measured by octanol/saline partition method. The influence of influx/efflux transporters on uptake was evaluated in the absence and presence of inhibitors of P-gp (GPV031), P-gp/BCRP (tariquidar and GF120918), P-gp/MRP1 (dipyridamole and daidzein), MRP1/2 (frusemide and genistein), hOATP/hOCTP (estrone-3-sulfate [E-3-S]) and hOATP/hOCTP/MRP (probenecid). The effects of a number of HPIs on uptake were also evaluated. Data from digitonin permeabilized cells allowed the evaluation of the contribution of cellular binding to total drug uptake, whereas the inhibitory effect of ATV on P-gp was assessed by daunomycin efflux/uptake assays.

Results: [(3)H]-ATV is lipophilic and accumulates in the cultured cells as follows: CEM>CEM(E1000)>CEM(VBL). Tariquidar, GF120918 and daidzein significantly increased the uptake of [(3)H]-ATV in the cultured cells. By contrast, only daidzein and tipranavir significantly increased uptake in PBMCs, with tariquidar and frusemide devoid of effects, whereas dipyridamole, E-3-S, GPV031 and genistein significantly decreased accumulation. ATV inhibits P-gp activity; manipulation of uptake with digitonin suggests binding of [(3)H]-ATV to P-gp.

Conclusions: [(3)H]-ATV is lipophilic, a P-gp, MRP and hOATP substrate and an inhibitor of P-gp. Concomitant administration of ATV with drugs and dietary components (for example, daidzein and genistein) that interact with these transporters could alter its pharmacokinetics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Anti-HIV Agents / pharmacokinetics*
  • Atazanavir Sulfate
  • Biological Transport / drug effects
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Line
  • Digitonin / pharmacology
  • HIV Infections / drug therapy
  • HIV Infections / metabolism*
  • Humans
  • Indicators and Reagents / pharmacology
  • Intracellular Space / metabolism
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Membrane Transport Modulators / pharmacology
  • Multidrug Resistance-Associated Proteins / antagonists & inhibitors
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Oligopeptides / pharmacokinetics*
  • Organic Anion Transporters / antagonists & inhibitors
  • Organic Anion Transporters / metabolism*
  • Pyridines / pharmacokinetics*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anti-HIV Agents
  • Indicators and Reagents
  • Membrane Transport Modulators
  • Multidrug Resistance-Associated Proteins
  • Oligopeptides
  • Organic Anion Transporters
  • Pyridines
  • Atazanavir Sulfate
  • Digitonin