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

• Published in: Journal of antimicrobial chemotherapy Vol. 67; no. 2; pp. 452 - 459
• Main Authors: YOUSEF, Jumana M, GONG CHEN, HILL, Prue A, NATIONAL, Roger L, JIAN LI
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.02.2012; Oxford Publishing Limited (England)
• Subjects: Animals; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - adverse effects; Anti-Bacterial Agents - pharmacokinetics; Antibiotics. Antiinfectious agents. Antiparasitic agents; Apoptosis; Ascorbic Acid - administration & dosage; Ascorbic Acid - pharmacology; Bacterial infections; Biological and medical sciences; Cells, Cultured; Colistin - administration & dosage; Colistin - adverse effects; Colistin - pharmacokinetics; Injections, Intravenous; Kidney Diseases - chemically induced; Kidney Diseases - prevention & control; Kidneys; Male; Medical sciences; Original Research; Pharmacology; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Rodents; Vitamin C; Vitamins - administration & dosage; Vitamins - pharmacology; rat kidney tubular cells; Ascorbic acid; Urinary system disease; Colistin; Rat; Cyclic peptides; Toxicity; vitamin C; Rodentia; Vitamin; polymyxin E; In vitro; Kidney; Prevention; Vertebrata; Antibiotic; Mammalia; Polypeptide; Cell death; Animal; Antibacterial agent; Pharmacokinetics; Cell; Apoptosis
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkr483

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. 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. The 24 h urinary excretion of N-acetyl-β-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 mM colistin 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). 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.