Received for publication July 20, 2007.
Revised August 17, 2007.
Accepted for publication August 17, 2007.

P-glycoprotein-mediated Active Efflux of the Anti-HIV1 Nucleoside Abacavir Limits Cellular Accumulation and Brain Distribution

Abstract

P-glycoprotein (P-gp) mediated efflux at the blood-brain barrier has been implicated in limiting the brain distribution of many anti-HIV1 drugs, primarily protease inhibitors, resulting in sub-optimal concentrations in this important sanctuary site. The objective of this study was to characterize the interaction of abacavir with P-gp and determine if P-gp is an important mechanism in limiting abacavir delivery to the CNS. In-vitro and in-vivo techniques were employed to characterize this interaction. Abacavir stimulated P-gp ATPase activity at high concentrations. The cellular accumulation of abacavir was significantly decreased by ~70% in MDCKII-MDR1 monolayers compared to wild-type cells and was completely restored by the P-gp inhibitors LY335979 and GF120918. Directional flux experiments indicated that abacavir had greater permeability in the basolateral-to-apical (B-to-A) direction (1.58E-05 cm/s) than in the apical-to-basolateral (A-to-B) direction (3.44E-06 cm/s) in MDR1-transfected monolayers. The directionality in net flux was abolished by both LY335979 and GF120918. In-vivo brain distribution studies showed that the AUC_plasma in mdr1a (-/-) CF-1 mutant mice was ~2-fold greater than AUC_plasma in the wild-type, while the AUC_brain in the mutant was 20-fold higher than wild-type. Therefore, the CNS drug targeting index (DTI), defined as the ratio of AUC brain-to-plasma for mutant over wild-type, was greater than 10. These data are the first in-vitro and in-vivo evidence that a nucleoside reverse transcriptase inhibitor is a P-gp substrate. The remarkable increase in abacavir brain distribution in P-gp deficient mutant mice over wild-type suggests that P-gp may play a significant role in restricting the abacavir distribution to the CNS.

Key words: ABC transporters, blood-brain barrier, blood-CNS transport, CNS pharmacokinetics, drug efflux, drug transport, membrane transport, p-glycoprotein, targeted delivery, transporters

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