Document Detail

Ascorbic acid protects against the nephrotoxicity and apoptosis caused by colistin and affects its pharmacokinetics.
MedLine Citation:
PMID:  22127588     Owner:  NLM     Status:  MEDLINE    
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-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).
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.
Jumana M Yousef; Gong Chen; Prue A Hill; Roger L Nation; Jian Li
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-11-28
Journal Detail:
Title:  The Journal of antimicrobial chemotherapy     Volume:  67     ISSN:  1460-2091     ISO Abbreviation:  J. Antimicrob. Chemother.     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-01-11     Completed Date:  2012-05-01     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  7513617     Medline TA:  J Antimicrob Chemother     Country:  England    
Other Details:
Languages:  eng     Pagination:  452-9     Citation Subset:  IM    
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.
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MeSH Terms
Anti-Bacterial Agents / administration & dosage,  adverse effects*,  pharmacokinetics
Ascorbic Acid / administration & dosage*,  pharmacology
Cells, Cultured
Colistin / administration & dosage,  adverse effects*,  pharmacokinetics
Injections, Intravenous
Kidney Diseases / chemically induced*,  prevention & control*
Rats, Sprague-Dawley
Vitamins / administration & dosage*,  pharmacology
Grant Support
R01A1070896//PHS HHS; R01AI079330/AI/NIAID NIH HHS
Reg. No./Substance:
0/Anti-Bacterial Agents; 0/Vitamins; 1066-17-7/Colistin; 50-81-7/Ascorbic Acid

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