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 [14C]nelfinavir, up to 37- and 4-fold, respectively, in a dose-dependent fashion. Similar effects in brain levels were also observed with 14C-labeled amprenavir, indinavir, and saquinavir. Because [14C]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.
Footnotes
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Send reprint requests to: Richard B. Kim, M.D., 572 MRB1 Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602. E-mail:richard.kim{at}mcmail.vanderbilt.edu
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This work was supported in part by U.S. Public Health Service Grants GM31304, GM54724, CA68485; the Deutsche Forschungsgemeinschaft (to C.W.); and a grant in-aid from Lilly Research Laboratories.
- Abbreviations used are::
- P-gp
- P-glycoprotein
- MDR
- multidrug resistance
- OATP
- human organic anion transporting polypeptide
- LY-335979
- (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinilone trihydrochloride
- Received November 18, 1999.
- Accepted February 28, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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