title: Melatonin attenuates colistin-induced nephrotoxicity in rats.
abstract: Colistin-induced nephrotoxicity is a dose-limiting adverse effect when colistin is used against Gram-negative pathogens. This study examined the nephroprotective effect of melatonin against colistin in rats. Rats (n = 7 per group) were treated intravenously twice daily with saline, colistin (at increasing doses from 0.5 to 4.0 mg/kg), melatonin (5 mg/kg), or both melatonin and colistin for 7 days. The severity of renal alteration was examined both biochemically and histologically. The effect of coadministration of melatonin on colistin pharmacokinetics was investigated. Significantly lower urinary N-acetyl-β-d-glucosaminidase excretion was observed from day 1 in the colistin-melatonin group compared to the colistin group (P < 0.0001). Plasma creatinine increased significantly (P = 0.023) only in the colistin group on day 6. Significant histological abnormalities (P < 0.0001) were detected only in the kidneys of the colistin group. Melatonin altered colistin pharmacokinetics; the total body clearance in the colistin-melatonin group (1.82 ± 0.26 ml/min/kg) was lower than in the colistin group (4.28 ± 0.93 ml/min/kg). This is the first study demonstrating the protective effect of melatonin against colistin-induced nephrotoxicity, which indicates that colistin-induced nephrotoxicity is mediated through oxidative stress. It also highlights the potential of coadministering an antioxidant to widen the therapeutic window of this very important last-line antibiotic.
authors.affiliation: Facility for Anti-Infective Drug Development and Innovation, Drug Delivery, Disposition, and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Jumana M
authors.initials: JM
authors.lastname: Yousef
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
authors.forename: Prue A
authors.initials: PA
authors.lastname: Hill
authors.forename: Roger L
authors.initials: RL
authors.lastname: Nation
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D000118:Acetylglucosaminidase / Q000652:urine; D000818:Animals; D003091:Colistin / Q000633:toxicity*; D003404:Creatinine / Q000097:blood; D007668:Kidney / Q000187:drug effects*; D008297:Male; D008550:Melatonin / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D003404:Creatinine; D000118:Acetylglucosaminidase; D008550:Melatonin; D003091:Colistin