RT Journal Article
SR Electronic
T1 DEPENDENCE OF NELFINAVIR BRAIN UPTAKE ON DOSE AND TISSUE CONCENTRATIONS OF THE SELECTIVE P-GLYCOPROTEIN INHIBITOR ZOSUQUIDAR IN RATS
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 653
OP 659
DO 10.1124/dmd.105.006536
VO 34
IS 4
A1 Bradley D. Anderson
A1 Melissa J. May
A1 Sherri Jordan
A1 Lin Song
A1 Michael J. Roberts
A1 Markos Leggas
YR 2006
UL http://dmd.aspetjournals.org/content/34/4/653.abstract
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