Role of kidney-specific organic anion transporters in the urinary excretion of methotrexate

Background. High-dose folinic acid is used to accelerate methotrexate elimi nation to avoid renal toxicity of the drug. The present study was carried o ut to examine the role of the renal organic anion transporters OAT-K1 and O AT-K2 in the urinary excretion of methotrexate, especially in the methotrex ate-folinic acid rescue therapy. Methods. Madin-Darby canine kidney cells stably expressing OAT-K1 and OAT-K 2 were used for the in vitro transport study; 5/6 nephrectomized rats were used to detect changes in mRNA expression levels of OAT-K1 and OAT-K2 and t o evaluate methotrexate pharmacokinetics under conditions of renal insuffic iency. Results. Methotrexate efflux mediated by these transporters in stable trans fectants was stimulated in the presence of extracellular folic acid and fol inic acid, suggesting that they could serve as anion exchangers to enhance the apical efflux of methotrexate. The mRNA expression levels of OAT-K1 and OAT-K2 were markedly diminished after 5/6 nephrectomy, but those of multid rug resistance associated protein 2, which could transport methotrexate, we re maintained. Renal clearance of methotrexate was markedly decreased in 5/ 6 nephrectomized rats compared with that in sham-operated rats. Additional folinic acid treatment resulted in a significant increase in methotrexate r enal clearance in sham-operated rats but not in 5/6 nephrectomized rats. Conclusions. The decreased expressions of OAT-K1 and OAT-K2 may be attribut able to the longer exposure to methotrexate and ineffective folinic acid re scue. In terms of contributing to patient safety, renal clearance of methot rexate, especially folinic acid-stimulated tubular secretion of the drug vi a these transporters, would be a key factor in methotrexate therapy.