Jumana M Yousef1, Gong Chen, Prue A Hill, Roger L Nation, Jian Li. 1. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.
Abstract
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.
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.
Authors: Jian Li; Robert W Milne; Roger L Nation; John D Turnidge; Timothy C Smeaton; Kingsley Coulthard Journal: Antimicrob Agents Chemother Date: 2003-05 Impact factor: 5.191
Authors: S M Garonzik; J Li; V Thamlikitkul; D L Paterson; S Shoham; J Jacob; F P Silveira; A Forrest; R L Nation Journal: Antimicrob Agents Chemother Date: 2011-05-09 Impact factor: 5.191
Authors: Jian Li; Robert W Milne; Roger L Nation; John D Turnidge; Kingsley Coulthard Journal: Antimicrob Agents Chemother Date: 2003-04 Impact factor: 5.191
Authors: Kevin J Downes; Molly Hayes; Julie C Fitzgerald; Gwendolyn M Pais; Jiajun Liu; Nicole R Zane; Stuart L Goldstein; Marc H Scheetz; Athena F Zuppa Journal: J Antimicrob Chemother Date: 2020-01-01 Impact factor: 5.790
Authors: Jiajun Liu; Gwendolyn M Pais; Sean N Avedissian; Annette Gilchrist; Andrew Lee; Nathaniel J Rhodes; Alan R Hauser; Marc H Scheetz Journal: Antimicrob Agents Chemother Date: 2020-04-21 Impact factor: 5.191
Authors: Mohammad A K Azad; Jesmin Akter; Kelly L Rogers; Roger L Nation; Tony Velkov; Jian Li Journal: Antimicrob Agents Chemother Date: 2015-01-26 Impact factor: 5.191