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Renal organic anion transporters, OAT-K1 and OAT-K2, are expressed specifically in the brushborder membranes of the proximal straight tubules. Both of them transported structurally unrelated compounds such as antitumor drug methotrexate, various endogenous organic anions (thyroid hormones, taurocholic acid and conjugated steroids), and an antiretroviral drug zidovudine, which possesses no typical anionic moiety. In addition, OAT-K1 and OAT-K2 showed bidirectional transport of substrates. Moreover, methotrexate efflux via these transporters was stimulated in the presence of extracellular folic acid-derivatives, suggesting that they could serve as anion exchangers to enhance the apical efflux of methotrexate.In the state of renal failure caused by 5/6 nephrectomy, the mRNA expression levels of OAT-K1 and OAT -K2 were significantly diminished, and the renal clearance of methotrexate was markedly decreased compared with that in sham-operated rats. Furthermore, additional folinic acid treatment resulted in a significant increase in methotrexate renal clearance in sham-operated rats, but not in 5/6 nephrectomized rats. These findings suggested that the decreased expressions of OAT-K1 and OAT-K2 were attributed to the longer exposure to methotrexate and invalidated folinic acid rescue in 5/6 nephrectomized rats. In conclusion, OAT-K1 and OAT-K2 may play important roles in the renal handling of hydrophobic anionic drugs.

Role of Renal Organic Anion Transporters, OAT-K1 aud OAT-K2, in the Urinary Excretion of Anionic Drugs.