GF120918, a P-glycoprotein modulator, increases the concentration of unbound amprenavir in the central nervous system in rats

Abstract

The goal of this study was to determine the distribution of unbound amprenavir in the central nervous system (CNS) of rats. The concentration of unbound amprenavir in the extracellular fluid of the brain and the blood was examined in the presence and absence of the MDR modulator GF120918 by microdialysis. The brain-to-blood ratio of amprenavir in the absence and presence of GF120918 was found to be significantly different (P < 0.003; 0.076 and 0.617, respectively). The use of the MDR modulator GF120918 could potentially increase the penetration of human immunodeficiency virus protease inhibitors into the CNS.

FIG. 1.

In vitro recovery of amprenavir (▪) and the loss of [¹⁴C]amprenavir (□) from CMA/12 microdialysis probes (means ± standard errors of the means; n = 3).

FIG. 2.

(a) Concentration-time profiles of unbound amprenavir (26.8 mg h⁻¹ kg⁻¹) in plasma (▪) and CNS (□) in a rat treated with vehicle (suspension for 4 consecutive days). (b) Concentration-time profiles of unbound amprenavir (26.8 mg h⁻¹ kg⁻¹) in plasma (▪) and CNS (□) in a rat treated with GF120918 (250 mg kg⁻¹ day⁻¹ for 4 consecutive days).

FIG. 3.

BBR time profile of amprenavir (26.8 mg h⁻¹ kg⁻¹) in rats treated with GF120918 (□) (250 mg kg⁻¹ day⁻¹ for 4 consecutive days) and rats treated with vehicle (▪) (suspension for 4 consecutive days) (means ± standard errors of the means; n = 5).