Abstract
We isolated cDNAs coding rat organic anion transporters, OAT-K1 and OAT-K2, expressed specifically in the brush-border membranes of the proximal straight tubules. In this study, we have examined the physiological roles of OAT-K1 and OAT-K2 in the urinary excretion of anionic drugs with the in vitro and in vivo experiments.
Methotrexate efflux via these transporters in the stable transfectants was stimulated in the presence of extracellular organic anions, 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 In addition, the renal clearance of methotrexate was markedly decreased in 5/6 nephrectomized rats, compared with that in sham-operated rats. Moreover, 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.
