PT  - JOURNAL ARTICLE
AU  - Anderson, Bradley D.
AU  - May, Melissa J.
AU  - Jordan, Sherri
AU  - Song, Lin
AU  - Roberts, Michael J.
AU  - Leggas, Markos
TI  - DEPENDENCE OF NELFINAVIR BRAIN UPTAKE ON DOSE AND TISSUE CONCENTRATIONS OF THE SELECTIVE P-GLYCOPROTEIN INHIBITOR ZOSUQUIDAR IN RATS
AID  - 10.1124/dmd.105.006536
DP  - 2006 Apr 01
TA  - Drug Metabolism and Disposition
PG  - 653--659
VI  - 34
IP  - 4
4099  - http://dmd.aspetjournals.org/content/34/4/653.short
4100  - http://dmd.aspetjournals.org/content/34/4/653.full
SO  - Drug Metab Dispos2006 Apr 01; 34
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics