title: Effects of obesity and sex on antimicrobial pharmacokinetics and acute kidney injury: validation of a preclinical model.
abstract: Obese patients may be at a greater risk for acute kidney injury (AKI) with the use of certain antimicrobial agents that are dosed by weight. Current preclinical models of AKI utilize the male rat within a narrow weight range that limits extrapolation of the generated results. We evaluated the pharmacokinetics and AKI potential of gentamicin in 14-week-old diet-induced obesity-prone (n = 40) and obesity-resistant (n = 40) rats of both sexes. Single daily doses of gentamicin (12.5, 18.75, or 25 mg/kg of body weight) or saline (control) were administered intraperitoneally for 14 doses. Blood samples were collected after doses 1, 7, and 14, assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and analyzed using a nonparametric population pharmacokinetic approach for gentamicin. Urine was collected after doses 1, 3, and 5 and assayed for kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) and normalized to creatinine (Cr) values. Histology was performed on all animals, and the degree of proximal tubular injury was graded. The mean (minimum, maximum) weight of the rats was 330 (136, 580) g. NGAL/Cr predicted AKI better than did KIM-1/Cr and was detectable in male rats after dose 1 and in obesity-prone female rats after dose 5. Proximal tubular injury by histology was significantly higher in male than in female rats. A significant relationship between the gentamicin area under the curve from zero to 24 hours (AUC(0-24)) estimates and the maximum NGAL/Cr ratio was observed. This preclinical model has the potential to aid with dose extrapolation for body size and improve assessment of the toxicology potential of antimicrobials in development.
authors.affiliation: Albany College of Pharmacy and Health Sciences, Albany, New York, USA. amit.pai@acphs.edu
authors.forename: Manjunath P
authors.initials: MP
authors.lastname: Pai
authors.forename: Wen Zhen
authors.initials: WZ
authors.lastname: Chen
authors.forename: Adinoyi
authors.initials: A
authors.lastname: Garba
authors.forename: Huadong
authors.initials: H
authors.lastname: Cui
authors.forename: Barbara
authors.initials: B
authors.lastname: Zaffo
authors.forename: Hassan A N
authors.initials: HA
authors.lastname: El-Fawal
authors.forename: Shaker A
authors.initials: SA
authors.lastname: Mousa
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology*; D000209:Acute-Phase Proteins / Q000652:urine; D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics*; D015815:Cell Adhesion Molecules / Q000652:urine; D003404:Creatinine / Q000652:urine; D005260:Female; D005839:Gentamicins / Q000097:blood / Q000493:pharmacokinetics*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000652:urine; D008297:Male; D009765:Obesity; D011518:Proto-Oncogene Proteins / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors
chemical_list: D000209:Acute-Phase Proteins; D000900:Anti-Bacterial Agents; D015815:Cell Adhesion Molecules; D003404:Creatinine; D005839:Gentamicins; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; C110936:Havcr1 protein, rat; C097278:Lcn2 protein, rat