Received for publication February 14, 2008.
Revised April 22, 2008.
Accepted for publication April 23, 2008.

Investigation of the Role of Abcg2/Bcrp1 on Pharmacokinetics and CNS Penetration of Abacavir (ABC) and Zidovudine (AZT) in the Mouse

Abstract

Many anti-HIV1 nucleoside reverse-transcriptase inhibitors (NRTIs) have low CNS distribution due in part to active efflux transport at the blood-brain barrier. We have previously shown that zidovudine (AZT) and abacavir (ABC) are in vitro substrates for the efflux transport protein Bcrp1. We evaluated the influence of Bcrp1 on plasma pharmacokinetics and brain penetration of zidovudine and abacavir in wild-type and Bcrp1-deficient (Bcrp1-/-) FVB mice. There was no difference in either the AUCplasma or the AUCbrain for zidovudine between the wild-type and Bcrp1 (-/-) mice. The AUCplasma of abacavir was 20% lower in the Bcrp1 (-/-) mice whereas the AUCbrain was 20% greater. This resulted in a 1.5-fold increase in abacavir brain exposure in the Bcrp1 (-/-) mice. The effect of selective and nonselective transport inhibitors on the ABC brain-to-plasma ratio at a single time point was evaluated. Ko143, GF120918, probenecid and Pluronic P85 increased abacavir plasma concentrations in the wild-type. Abacavir plasma concentrations in Bcrp1 (-/-) mice were increased by LY335979, GF120918 and probenecid, but not Ko143. Brain-to-plasma concentration ratios in both the wild-type and Bcrp1 (-/-) mice were increased by P-gp inhibitors LY335979 and GF120918, but not BCRP selective inhibitors. These data indicate that deletion of Bcrp1 has little influence on the pharmacokinetics or brain penetration of AZT. However, for abacavir, deletion of Bcrp1 reduces plasma exposure and enhances brain penetration. These findings suggest that Bcrp1 does not play a significant role in limiting the CNS distribution of zidovudine and abacavir, however brain penetration of abacavir is dependent on p-glycoprotein mediated efflux.

Key words: ABC transporters, blood-brain barrier, blood-CNS transport, drug distribution, drug transport, membrane transport, p-glycoprotein, transgenic models