Abcg2/Bcrp1 Mediates the Polarized Transport of Antiretroviral Nucleosides Abacavir and Zidovudine

Abstract

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 nucleoside reverse transcriptase inhibitors with the Abcg2/Bcrp1 transporter, the murine homolog of human breast cancer resistance protein (BCRP), using a Bcrp1-trans- (6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1,2:1,6]pyrido[3,4-b]indol-3-yl)-propionic acid tert-butyl ester) was observed with an EC 50 of 121 ؎ 5 nM for ABC and 19.2 ؎ 1.5 nM for AZT (Hill coefficient ϳ3-6). 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 antiretroviral 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.

Contribution of the drug transporter ABCG2 (breast cancer resistance protein) to resistance against anticancer nucleosides

“…Our preliminary results for 6-MP confirm this assumption. 5 Moreover, while our work was being finished, Pan et al (48) reported evidence that the antiretroviral nucleosides zidovudine and abacavir are transported as nucleosides as well by Abcg2.…”

Stereoselective Interaction of Pantoprazole with ABCG2. II. In Vitro Flux Analysis

“…Initial attempts to fit flux to permutations of the MichaelisMenten equation as a function of donor concentration resulted in fits that did not mimic the observed data. Fitting flux to donor concentrations suggested an apparent cooperative interaction (i.e., Hill coefficient) with the transporter (Pan et al, 2007). The driving force for an apical efflux transporter, such as rAbcg2/ABCG2, is cellular and not donor concentration.…”

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

“…Overexpression of Bcrp/ BCRP reduces accumulation and confers resistance to mitoxantrone, daunorubicin, doxorubicin, topotecan, and rhodamine 123 (Doyle et al, 1998;Allen et al, 1999;Litman et al, 2000;Wang et al, 2003c). Bcrp/BCRP transports a wide range of substrates, including photosensitizers, antibiotics, antivirals, natural products, statins, and carcinogens (Table 7) (Merino et al, 2005aRobey et al, 2005;Huang et al, 2006a;Ando et al, 2007;Enokizono et al, 2007;Pan et al, 2007;Myllynen et al, 2008). BCRP also transports the fluorescent dye Hoechst 33342, which is used to label stem cell populations (Table 1).…”