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Vol. 294, Issue 3, 844-849, September 2000
Department of Pharmacology and Toxicology, Kyorin University School
of Medicine, Mitaka, Tokyo, Japan (S.W., M.T., T.S., S.H.C., Y.K.,
H.E.); Pharmaceutical Development Research Laboratory, Tanabe Seiyaku
Co. Ltd., Toda, Saitama, Japan (M.T.); and Department of Toxicology,
Kyoritsu College of Pharmacy, Minato-ku, Tokyo, Japan (S.W., M.K.)
Organic anion transporter 1 (OAT1) is a
p-aminohippurate/dicarboxylate exchanger that plays a
primary role in the tubular secretion of endogenous and exogenous
organic anions. OAT1 is located in the basolateral membrane of the
proximal tubular cells and mediates the uptake of various organic
anions from the peritubular fluid. In this study, we investigated the
transport of antiviral nucleoside analogs via rat OAT1 (rOAT1) using a
heterologous expression 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. The affinity
of rOAT1 for AZT and ACV was determined to be 68 and 242 µM,
respectively. Five other antiviral agents that we studied (zalcitabine,
didanosine, lamivudine, stavudine, and trifluridine) were also shown to
be transported by rOAT1, whereas foscarnet, a phosphate analog, was not. The aforementioned 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.
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