Protective effect of morin on the imipenem-induced nephrotoxicity in rabbits

The present study investigated the protective effect of morin, a natural flavonoid, on the imipenem-induced nephrotoxicity in rabbits. Nephrotoxicity of imipenem was examined after the intravenous administrations of imipenem (200 mg/kg) to rabbits in the presence and the absence of morin (12, 25, 50 mg/kg, p.o.). Cytotoxicity of imipenem was also examined in the presence and the absence of morin (100 mu M) by using MDCK cells overexpressing human organic anion transporter 1 and 3 (MDCK/hOAT1 or MDCK/hOAT3). Intravenous dosing of imipenem alone induced severe proximal tubular necrosis in rabbits, however, the concurrent use of morin (25 or 50 mg/kg, p.o,) significantly suppressed the histopathological damage in the kidney induced by imipenem. While imipenem was not cytotoxic in MDCK/hOAT1 cells over the tested concentrations up to 10 mM, it showed significant cellular toxicity with CC(50) of 0.77 mM in MDCK/hOAT3 cells, implying that OAT3 may involve more actively in the imipenem-induced nephrotoxicity. In addition, the cellular toxicity of imipenem decreased by approximately 20 folds in the presence of morin in MDCK/hOAT3 cells. In conclusion, the present study suggests that morin might be beneficial to reduce the nephrotoxicity of imipenem, at least in part, via the inhibition of OAT3-mediated renal excretion of imipenem.