title: HIV-1 protease inhibitors are substrates for the MDR1 multidrug transporter.
abstract: 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.
authors.affiliation: Laboratory of Cell Biology, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: C G
authors.initials: CG
authors.lastname: Lee
authors.forename: M M
authors.initials: MM
authors.lastname: Gottesman
authors.forename: C O
authors.initials: CO
authors.lastname: Cardarelli
authors.forename: M
authors.initials: M
authors.lastname: Ramachandra
authors.forename: K T
authors.initials: KT
authors.lastname: Jeang
authors.forename: S V
authors.initials: SV
authors.lastname: Ambudkar
authors.forename: I
authors.initials: I
authors.lastname: Pastan
authors.forename: S
authors.initials: S
authors.lastname: Dey
mesh_terms: D016475:3T3 Cells; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000345:Affinity Labels; D000818:Animals; D001386:Azides / Q000378:metabolism; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D002294:Carcinoma, Squamous Cell; D018432:Drug Resistance, Multiple; D004789:Enzyme Activation / Q000187:drug effects; D019450:Genes, MDR; D017320:HIV Protease Inhibitors / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D007457:Iodine Radioisotopes; D051379:Mice; D011224:Prazosin / Q000031:analogs & derivatives / Q000378:metabolism; D018411:Spodoptera / Q000235:genetics; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D001386:Azides; D017320:HIV Protease Inhibitors; D007457:Iodine Radioisotopes; D014747:Vinblastine; C041552:azidoprazosin; D000251:Adenosine Triphosphatases; D011224:Prazosin