Obesity as a risk factor in drug-induced organ injury. V. Toxicokinetics of gentamicin in the obese overfed rat.
Obese human patients and obese overfed rats treated chronically with gentamicin suffer greater renal injury than nonobese patients and control animals. To understand the mechanism of this heightened susceptibility to the nephrotoxic effects of gentamicin, this study examines the plasma-time course and renal uptake of gentamicin in control and obese overfed rats following a single bolus dose. Gentamicin was administered ip to control rats at 30 mg/kg total body mass and to obese rats at 30 mg/kg ideal body mass plus 40% of excess body mass. Following gentamicin dosing, only 1 of 11 concentration-time points taken over 6/hr postdosing was different between control and obese groups. In addition, the area under the plasma concentration curve extrapolated to infinite time was not different between obese and control rats (mean +/- SD of 4.47 +/- 0.85 vs. 4.13 +/- 0.35 mg.min.ml-1, p greater than 0.5). The gentamicin plasma concentrations after 6 hr were less than 1 microgram/ml and not different between the groups; however, the concentration of gentamicin in the kidneys was 33% greater in obese than control rats at this time (324 +/- 66.9 vs. 244 +/- 34.7 micrograms/g, p less than 0.05). The fraction of dose and the total amount of drug that accumulated in the kidneys were also greater in the obese rats (42 and 72% increases). Considered with the results of previous studies, it appears that obese overfed rats sustain more severe nephrotoxicity following comparable plasma gentamicin exposure because of increased renal uptake and/or retention of drug.
Department of Pharmaceutics, School of Pharmacy, State University of New York.
D E
DE
Salazar
J J
JJ
Schentag
G B
GB
Corcoran
D000042:Absorption; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D005839:Gentamicins / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009765:Obesity / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012044:Regression Analysis
D005839:Gentamicins; D003404:Creatinine