Rat multispecific organic anion transporter 1 (rOAT1) transports zidovudine, acyclovir, and other antiviral nucleoside analogs

Organic anion transporter 1 (OAT1) is a p-aminohippurate/ dicarboxylate exc hanger that plays a primary role in the tubular secretion of endogenous and exogenous organic anions. OAT1 is located in the basolateral membrane of t he proximal tubular cells and mediates the uptake of various organic anions from the peritubular fluid. In this study, we investigated the transport o f antiviral nucleoside analogs via rat OAT1 (rOAT1) using a heterologous ex pression system in Xenopus laevis oocytes. Oocytes injected with rOAT1 cRNA showed significantly higher uptake of zidovudine (AZT) and acyclovir (ACV) than control oocytes. rOAT1-mediated uptake of AZT and ACV was probenecid- sensitive and increased by the outwardly directed gradient of glutarate. Th e affinity of rOAT1 for AZT and ACV was determined to be 68 and 242 mu M, r espectively. Five other antiviral agents that we studied (zalcitabine, dida nosine, lamivudine, stavudine, and trifluridine) were also shown to be tran sported by rOAT1, whereas foscarnet, a phosphate analog, was not. The afore mentioned nucleoside analogs lack a typical anionic group and are not very hydrophobic. This study demonstrates extension of the substrate spectrum of rOAT1 and provides a molecular basis for the pharmacokinetics of antiviral nucleoside analogs.