TY - JOUR T1 - Equilibrative nucleoside transporter 1 (ENT1, SLC29A1) facilitates transfer of the antiretroviral drug abacavir across the placenta JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.118.083329 SP - dmd.118.083329 AU - Lukas Cerveny AU - Zuzana Ptackova AU - Martina Ceckova AU - Rona Karahoda AU - Sara Karbanova AU - Lucie Jiraskova AU - Susan L Greenwood AU - Jocelyn D Glazier AU - Frantisek Staud Y1 - 2018/01/01 UR - http://dmd.aspetjournals.org/content/early/2018/08/10/dmd.118.083329.abstract N2 - Abacavir is a preferred antiretroviral drug for preventing mother-to-child HIV transmission; however, mechanisms of its placental transfer have not been satisfactorily described to date. Because abacavir is a nucleoside-derived drug, we hypothesized that the nucleoside transporters, ENTs (SLC29A) and/or Na+ dependent CNTs (SLC28A), may play a role in its passage across the placenta. To test this hypothesis, we performed uptake experiments using BeWo cell line, human fresh villous fragments and microvillous plasma membrane (MVM) vesicles. Employing endogenous substrates of nucleoside transporters, [3H] adenosine (ENTs, CNT2, and CNT3) and [3H] thymidine (ENTs, CNT1, and CNT3), we showed significant activity of ENT1 and CNT2 in BeWo cells while experiments in the villous fragments and MVM vesicles, representing model of apical membrane of syncytiotrophoblast, revealed only ENT1 activity. When testing [3H] abacavir uptakes, we showed that of nucleoside transporters, ENT1 plays the dominant role in abacavir uptake into placental tissues, whereas contribution of Na+ dependent transport, most likely mediated by CNTs, was observed only in BeWo cells. Subsequent experiments with dually perfused rat term placentas showed that Ent1 contributes significantly to overall [3H] abacavir placental transport. Finally, we quantified the expression of SLC29A in first- and third-trimester placentas, revealing that SLC29A1 is the dominant isoform. Neither SLC29A1 nor SLC29A2 expression changed over the course of placental development, but there was considerable inter-individual variability in their expression. Therefore, drug-drug interactions and the effect of inter-individual variability in placental ENT1 expression on abacavir disposition into fetal circulation should be further investigated to guarantee safe and effective abacavir-based combination therapies in pregnancy. ER -