Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes.
Article Details
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Choo EF, Leake B, Wandel C, Imamura H, Wood AJ, Wilkinson GR, Kim RB
Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes.
Drug Metab Dispos. 2000 Jun;28(6):655-60.
- PubMed ID
- 10820137 [ View in PubMed]
- Abstract
HIV protease inhibitors have proven remarkably effective in treating HIV-1 infection. However, some tissues such as the brain and testes (sanctuary sites) are possibly protected from exposure to HIV protease inhibitors due to drug entry being limited by the membrane efflux transporter P-glycoprotein, located in the capillary endothelium. Intravenous administration of the novel and potent P-glycoprotein inhibitor LY-335979 to mice (1-50 mg/kg) increased brain and testes concentration of [(14)C]nelfinavir, up to 37- and 4-fold, respectively, in a dose-dependent fashion. Similar effects in brain levels were also observed with (14)C-labeled amprenavir, indinavir, and saquinavir. Because [(14)C]nelfinavir plasma drug levels were only modestly increased by LY-335979, the increase in brain/plasma and testes/plasma ratios of 14- to 17- and 2- to 5-fold, respectively, was due to increased tissue penetration. Less potent P-glycoprotein inhibitors like valspodar (PSC-833), cyclosporin A, and ketoconazole, as well as quinidine and verapamil, had modest or little effect on brain/plasma ratios but increased plasma nelfinavir concentrations due to inhibition of CYP3A-mediated metabolism. Collectively, these findings provide "proof-of-concept" for increasing HIV protease inhibitor distribution into pharmacologic sanctuary sites by targeted inhibition of P-glycoprotein using selective and potent agents and suggest a new therapeutic strategy to reduce HIV-1 viral replication.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Indinavir P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails Ketoconazole P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Nelfinavir P-glycoprotein 1 Protein Humans NoSubstrateInhibitorInducerDetails Quinidine P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorDetails Ritonavir P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails Saquinavir P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails - Binding Properties
Drug Target Property Measurement pH Temperature (°C) Cyclosporine P-glycoprotein 1 IC 50 (nM) 1300 N/A N/A Details Indinavir P-glycoprotein 1 IC 50 (nM) 44000 N/A N/A Details Ketoconazole P-glycoprotein 1 IC 50 (nM) 1200 N/A N/A Details Ritonavir P-glycoprotein 1 IC 50 (nM) 3800 N/A N/A Details Saquinavir P-glycoprotein 1 IC 50 (nM) 6500 N/A N/A Details Verapamil P-glycoprotein 1 IC 50 (nM) 2100 N/A N/A Details - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareAzithromycinNelfinavir The serum concentration of Azithromycin can be increased when it is combined with Nelfinavir.