Obesity as a risk factor in drug-induced organ injury. III. Increased liver and kidney injury by furosemide in the obese overfed rat.
Effects of the diuretic drug furosemide were examined in obese animals to evaluate the hypothesis that organ damage by reactive drug metabolites may be potentiated by this disease. Obese overfed Sprague-Dawley rats that were treated ip with 450 mg/kg furosemide on the basis of total body mass suffered a 58% mortality rate over 24 h. This contrasted with 0% mortality in animals of normal body mass. On the basis of median histopathology scores, organ necrosis was judged to be greater in the liver (2+) and kidneys (1+) of obese rats than in the liver (1+) and kidneys (less than 1+) of normal controls (p less than 0.05). Obese animals demonstrated a fourfold rise in fat mass over controls. The low solubility of furosemide in lipid makes it probable that aggravated drug toxicity in obese rats dosed to total body mass resulted in part from elevated furosemide concentrations in lean body mass. In a subsequent study designed to minimize this possibility, furosemide was administered on the basis of fat-free body mass to equalize initial drug exposure in obese and control rats. Even with this downward dosage adjustment, obese animals suffered increased hepatic necrosis (median score of 2+ versus 0 in treated controls), greater impairment of renal function (plasma creatinine concentration of 2.41 mg/dl versus 0.96 mg/dl in treated controls), and more extensive enzymuria (enzyme excretion 175-300% more elevated than in treated controls). In conclusion, obese rats appear to be at increased risk of furosemide-induced liver and kidney injury due to at least two factors: (1) increased exposure of target organs in lean body mass to furosemide when the dosing of this poorly lipophilic drug was based on total body mass, and (2) increased susceptibility of target organs in lean body mass to furosemide injury when dosing was adjusted downward to reflect fat-free body mass and to equalize initial drug exposure.
Corcoran
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GB
Department of Pharmaceutics, School of Pharmacy, State University of New York, Buffalo 14260.
Salazar
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DE
Chan
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D000818:Animals; D004032:Diet; D005665:Furosemide / Q000493:pharmacokinetics / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009765:Obesity / Q000097:blood / Q000503:physiopathology*; D051381:Rats; D011919:Rats, Inbred Strains; D012307:Risk Factors; D013194:Staining and Labeling
D005665:Furosemide