Received for publication December 11, 2006.
Revised April 12, 2007.
Accepted for publication April 13, 2007.

Abcg2/Bcrp1 mediates the polarized transport of anti-retroviral nucleosides Abacavir and Zidovudine

Abstract

The bioavailability and targeted distribution of abacavir (ABC) and zidovudine (AZT) to viral reservoirs may be influenced by efflux transporters. The purpose of this study was to characterize the interaction of these NRTIs with the Abcg2/Bcrp1 transporter, the murine homolog of human BCRP, using a Bcrp1-transfected MDCKII cell model. Intracellular accumulation of ABC and AZT was significantly reduced by ~90% and ~70%, respectively, in Bcrp1-transfected cells when compared to the wild-type cells. Both ABC and AZT showed significantly increased basolateral-to-apical (B-to-A) and decreased apical-to-basolateral (A-to-B) transport in Bcrp1 cells when compared to wild-type directional flux. The efflux ratio (ratio of B-to-A to A-to-B) in Bcrp1-transfected cells was 22 for ABC and 11 for AZT. GF120918 inhibited this difference in accumulation between the two cell variants with an EC₅₀ of 1.32 ± 0.3µM for ABC and 0.31 ± 0.1µM for AZT. Potent and highly cooperative inhibition by Ko143 was observed with an EC₅₀ of 121 ± 5nM for ABC and 19.2 ± 1.5nM for AZT (Hill coefficient ~ 3-6). Probenecid, an organic anion inhibitor known to influence AZT biodistribution, had no effect on cellular accumulation in the Bcrp1 model. These studies characterize the Bcrp1-mediated transport of ABC and AZT and show that prototypical BCRP inhibitors GF120918 and Ko143 can inhibit the Bcrp1-mediated transport of these important anti-retroviral compounds. The functional expression of BCRP at critical barriers, such as the intestinal enterocytes, brain capillary endothelium, and target lymphocytes, could influence the bioavailability and targeted delivery of these drugs to sanctuary sites.

Key words: ABC transporters, active transport, blood-brain barrier, membrane barriers, permeability, targeted delivery, transporters