Abstract
Most reverse transcriptase and protease inhibitors used in highly active antiretroviral therapy for treating human immunodeficiency virus (HIV) infections exhibit poor penetration into the brain, raising the concern that the brain may be a sanctuary site for the development of resistant HIV variants. This study explores the relationship between the dose and plasma and brain concentrations of zosuquidar and the effect of this selective P-glycoprotein inhibitor on central nervous system penetration of the HIV protease inhibitor nelfinavir maintained at steady state by intravenous infusions in rats. Nelfinavir was infused (10 mg/kg/h) for up to 10 h with or without concurrent administration of an intravenous bolus dose of 2, 6, or 20 mg/kg zosuquidar given at 4 h. Brain tissue and plasma were analyzed for both drug concentrations. Brain tissue/plasma nelfinavir concentration ratios (uncorrected for the vascular contribution) increased nonlinearly with zosuquidar dose from 0.06 ± 0.03 in the absence of zosuquidar and 0.09 ± 0.02 between 2 and 6 h after 2 mg/kg zosuquidar to 0.85 ± 0.19 after 6 mg/kg and 1.58 ± 0.67 after 20 mg/kg zosuquidar. Zosuquidar brain tissue/plasma concentration ratios exhibited a similar abrupt increase from 2.8 ± 0.3 after a 2 mg/kg dose to ∼15 after the 6 and 20 mg/kg doses. The apparent threshold in the plasma concentration of zosuquidar necessary to produce significant enhancement in brain uptake of nelfinavir appears to be close to the plasma concentrations associated with the maximum tolerated dose reported in the literature after repeated dosing of zosuquidar in patients.
Footnotes
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This work was supported by National Institutes of Health Grant R01 NS39178. Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.006536.
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ABBREVIATIONS: HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus; CNS, central nervous system; MDR, multidrug resistance; GF120918, N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide; LY335979·3HCl, (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzo-suber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride; HPLC, high-performance liquid chromatography; DMSO, dimethyl sulfoxide; BCRP, breast-cancer resistance protein; AUC, area under the curve.
- Received July 13, 2005.
- Accepted January 20, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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