Methionine Ameliorates Polymyxin-induced Nephrotoxicity by Attenuating Cellular Oxidative Stress [PublishAheadOfPrint]

Polymyxins are a last-line defence against multidrug-resistant Gram-negative pathogens. Recent pharmacological data show that intravenous polymyxins can cause nephrotoxicity in up to 60% of patients, and plasma concentrations of polymyxins are suboptimal in a large proportion of patients with the currently recommended dosage regimens. Simply increasing the daily dose of polymyxins is not possible due to nephrotoxicity. This study aimed to examine the protective effect of methionine against polymyxin-induced nephrotoxicity. Methionine (400 mg/kg), polymyxin B (35 mg/kg), a combination of methionine (100 or 400 mg/kg) and polymyxin B, and saline were administered in mice twice daily over 3.5 days. Kidneys were collected immediately at the end of the experiment for histological examination. Effect of methionine on the pharmacokinetics of polymyxin B was investigated in rats. Attenuation of polymyxin B (0.75 mM) induced mitochondrial superoxide production by methionine (10.0 mM) was examined in rat kidney cells (NRK-52E). Histological results revealed that polymyxin-induced nephrotoxicity in mice was ameliorated by methionine in a dose-dependent manner. Methionine doses were well tolerated in mice and rats, and the pharmacokinetics of polymyxin B in rats was not affected by methionine. In the polymyxin B + methionine group, the total body clearance of polymyxin B was very similar to that of polymyxin B alone (3.71±0.57 vs 3.12±1.66 mL/min/kg, P >0.05). Substantial attenuation of polymyxin-induced mitochondrial superoxide production in NRK-52E cells was observed following pre-treatment with methionine. Our results demonstrate that co-administration of methionine significantly ameliorated polymyxin-induced nephrotoxicity and decreased mitochondrial superoxide production in renal tubular cells.

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