Obesity as a risk factor in drug-induced organ injury. IV. Increased gentamicin nephrotoxicity in the obese overfed rat.
Obese humans suffer from excessive organ dysfunction, altered drug pharmacokinetics and may be at increased risk of various drug toxicities. A recent report shows that gentamicin nephrotoxicity in critically ill patients is more frequent and more severe than usual in individuals who are substantially overweight. The present study utilizes an overfed rat model to examine the influence of obesity on the nephrotoxic potential of gentamicin. After 52 weeks on an energy-dense diet, obese animals outweighed pellet controls by more than 80% (913 +/- 86 vs. 507 +/- 52 g; X +/- S.D., n = 7). When animals were treated twice daily for 6 days with 30 mg/kg of gentamicin i.p. based on total body mass, obese rats sustained more cortical necrosis than control (median score 3+ vs. 0), higher serum creatinine (4.36 +/- 2.72 vs. 0.71 +/- 0.17) and greater creatinine adjusted N-acetyl hexosaminidase excretion. The impact of obesity on intrinsic susceptibility to gentamicin nephrotoxicity was assessed by dosing animals for 5 days to ideal body mass plus 40% of excess body mass, the current clinical practice for achieving normal gentamicin concentrations in obese patients. Obese rats again sustained more frequent and severe cortical necrosis (2+ vs. 0) and excreted more N-acetyl hexosaminidase than control animals. Urine pH averaged 1.7 U below normal in obese animals, but restoration to normal values by 2 weeks on the pellet diet did not diminish the toxicity increase. Results from the overfed rat closely resemble the recent clinical observation that obese patients sustain more frequent and severe kidney damage from aminoglycoside antibiotics.(ABSTRACT TRUNCATED AT 250 WORDS)
Corcoran
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GB
Department of Pharmaceutics, School of Pharmacy, State University of New York, Buffalo.
Salazar
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DE
D000118:Acetylglucosaminidase / Q000652:urine; D000818:Animals; D005839:Gentamicins / Q000378:metabolism / Q000633:toxicity*; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009765:Obesity / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011919:Rats, Inbred Strains; D012307:Risk Factors
D005839:Gentamicins; D000118:Acetylglucosaminidase