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

Abstract

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 microM) 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.

Flavonoids as modulators of metabolic enzymes and drug transporters

“…All of these data suggest that flavonoids might protect against renal injury by inhibiting OAT1/OAT3‐mediated renal uptake of nephrotoxic drugs. The nephroprotective potential of morin was confirmed in animal studies: oral morin reduced the nephrotoxicity of intravenous imipenem (carbapenem antibiotic, OAT3 substrate) by inhibiting its OAT3‐mediated accumulation in the renal tubules …”

Impact of renal impairment and human organic anion transporter inhibition on pharmacokinetics, safety and tolerability of relebactam combined with imipenem and cilastatin

“…It was also demonstrated that urinary excretion was the major route of elimination for REL, similar to what was observed for imipenem and cilastatin, providing rationale for characterizing the impact of renal impairment (RI) on the PK of REL and the IMI/REL combination. In addition, both REL and imipenem undergo active renal secretion and REL was shown to be a substrate of human organic anion transporter 3 (OAT3); therefore, it is important to determine if potential drug–drug interactions with probenecid, a prototypic OAT inhibitor, have an impact on exposure . In a previous PK study, coadministration of imipenem with probenecid resulted in a mild increase (15%) in drug exposure .…”

Flavonoid conjugates interact with organic anion transporters (OATs) and attenuate cytotoxicity of adefovir mediated by organic anion transporter 1 (OAT1/SLC22A6)

“…This suggests that flavonoids have the potential to limit the severity of drug-induced renal injury via the inhibition of OAT1. Lin et al [44] also reported that the flavonoid morin protected against imipenem-induced nephrotoxicity, via the inhibition of OAT3-mediated accumulation of this antibiotic. Alternatively, flavonoids may attenuate drug-induced renal damage via free radical scavenging [45,46] or anti-apoptotic M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 mechanisms [47].…”