Organic anion transporters 1 (OAT1) and OAT3 meditated the protective effect of rhein on methotrexate-induced nephrotoxicity
Rhein is identified as a major metabolite of diacerein, a prodrug used in the treatment of osteoarthritis. Methotrexate (MTX) is a highly toxic drug with a low therapeutic index. MTX and diacerein are used concomitantly in clinical practice for the treatment of rheumatoid arthritis. The purpose of this study was to investigate organic anion transporters (OAT)-mediated effect of rhein on the disposition of MTX, as well as to clarify the changes in nephrotoxicity of MTX when given rhein together. Concomitant administration of rhein could strongly increase the systemic exposure in rats. Similarly, MTX accumulation was markedly inhibited by rhein in rat kidney slices and hOAT1/3-HEK293 cell, indicating that OAT1 and OAT3 were involved in the drug–drug interaction (DDI) in the kidney. Additionally, concomitant administration of rhein attenuated cytotoxic effects of MTX in hOAT1/3-HEK293 cells, and alleviated nephrotoxicity caused by MTX in rats. In conclusion, rhein decreased renal elimination of MTX by inhibiting OAT1 and OAT3, and alleviated MTX-induced renal toxicity in vivo.