Ascorbic acid protects against the nephrotoxicity and apoptosis caused by colistin and affects its pharmacokinetics

Objectives: The use of colistin in the treatment of life-threatening Gram-negative infections is associated with a high rate of nephrotoxicity that is dose limiting. This study aimed to examine the nephroprotective effect of ascorbic acid against colistin-induced nephrotoxicity. Methods: Rats were treated intravenously twice daily with saline, colistin (cumulative dose of 36.5 mg/kg), a combination of ascorbic acid (50 or 200 mg/kg) and colistin, or ascorbic acid (200 mg/kg) over 7 days. Colistin-induced apoptosis was examined in rats over 5 days and in vitro using rat renal proximal tubular cells NRK-52E over 24 h with and without ascorbic acid. The effect of co-administered ascorbic acid on colistin pharmacokinetics was investigated. Results: The 24 h urinary excretion of N-acetyl-beta-D-glucosaminidase, a sensitive marker for tubular damage, was significantly lower (P<0.0001) in the colistin/ascorbic acid 200 mg/kg group. Significant histological abnormalities (P<0.01) were detected only in the kidneys of the colistin group, which also had the highest percentage (30.6 +/- 7.8%) of apoptotic cells (P<0.005). In the cell culture studies, the percentage of apoptotic cells was significantly higher in the presence of 0.1 mMcolistin alone (51.8 +/- 2.0%; P<0.0001) than in the presence of ascorbic acid, which decreased the apoptotic effect in a concentration-dependent manner. Ascorbic acid (200 mg/kg) altered colistin pharmacokinetics, as the total body clearance decreased from 3.78 +/- 0.36 mL/min/kg (colistin group) to 2.46 +/- 0.57 mL/min/kg (P=0.0024). Conclusions: This is the first study demonstrating the protective effect of ascorbic acid against colistin-induced nephrotoxicity and tubular apoptosis. Co-administration of ascorbic acid has the potential to increase the therapeutic index of colistin.