HIV-1 protease inhibitors are substrates for the MDR1 multidrug transporter

Biochemistry. 1998 Mar 17;37(11):3594-601. doi: 10.1021/bi972709x.


The FDA approved HIV-1 protease inhibitors, ritonavir, saquinavir, and indinavir, are very effective in inhibiting HIV-1 replication, but their long-term efficacy is unknown. Since in vivo efficacy depends on access of these drugs to intracellular sites where HIV-1 replicates, we determined whether these protease inhibitors are recognized by the MDR1 multidrug transporter (P-glycoprotein, or P-gp), thereby reducing their intracellular accumulation. In vitro studies in isolated membrane preparations from insect cells infected with MDR1-expressing recombinant baculovirus showed that these inhibitors significantly stimulated P-gp-specific ATPase activity and that this stimulation was inhibited by SDZ PSC 833, a potent inhibitor of P-gp. Furthermore, photoaffinity labeling of P-gp with the substrate analogue [125I]iodoarylazidoprazosin (IAAP) was inhibited by all three inhibitors. Cell-based approaches to evaluate the ability of these protease inhibitors to compete for transport of known P-gp substrates showed that all three HIV-1 protease inhibitors were capable of inhibiting the transport of some of the known P-gp substrates but their effects were generally weaker than other documented P-gp modulators such as verapamil or cyclosporin A. Inhibition of HIV-1 replication by all three protease inhibitors was reduced but could be restored by MDR1 inhibitors in cells expressing MDR1. These results indicate that the HIV-1 protease inhibitors are substrates of the human multidrug transporter, suggesting that cells in patients that express the MDR1 transporter will be relatively resistant to the anti-viral effects of the HIV-1 protease inhibitors, and that absorption, excretion, and distribution of these inhibitors in the body may be affected by the multidrug transporter.

MeSH terms

  • 3T3 Cells
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology
  • Adenosine Triphosphatases / metabolism
  • Affinity Labels
  • Animals
  • Azides / metabolism
  • Binding, Competitive
  • Biological Transport / drug effects
  • Carcinoma, Squamous Cell
  • Drug Resistance, Multiple*
  • Enzyme Activation / drug effects
  • Genes, MDR*
  • HIV Protease Inhibitors / antagonists & inhibitors
  • HIV Protease Inhibitors / metabolism*
  • HIV Protease Inhibitors / pharmacology
  • HIV-1 / enzymology*
  • Humans
  • Iodine Radioisotopes
  • Mice
  • Prazosin / analogs & derivatives
  • Prazosin / metabolism
  • Spodoptera / genetics
  • Substrate Specificity
  • Tumor Cells, Cultured
  • Vinblastine / pharmacology


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Affinity Labels
  • Azides
  • HIV Protease Inhibitors
  • Iodine Radioisotopes
  • Vinblastine
  • azidoprazosin
  • Adenosine Triphosphatases
  • Prazosin