Renal handling of 5-nitrofuran nephrotoxins in the rat.
Formic acid 2-[4-(5-nitro-2-furyl)-2-thiazolyl)-hydrazide (FNT) and 3-hydroxymethyl-1-([3-(5-nitro-2-furyl)-allydidene]amino)hydantoin (HMN) were investigated to determine whether differences in the renal handling of these two chemicals might provide evidence to explain their different patterns of toxicity and carcinogenicity. The isolated perfused rat kidney and whole animal were used. In the isolated perfused rat kidney, both FNT and HMN had similar half-lives (t1/2) but the urinary excretion and renal clearance of HMN (2.1 +/- 0.4 greater than those of FNT (0.2 +/- 0.1 nmol/min and 0.06 +/- 0.01 ml/min, respectively). Probenecid increased the t1/2 and decreased the metabolic clearance of HMN but did not have any effect on FNT t1/2 or clearance. These differences in excretion of FNT and HMN could not be explained on the basis of protein binding. The total clearances of FNT and HMN were similar and significantly higher than that of the 5-nitrofuran bladder carcinogen ANFT. In the whole animal, the urinary excretion of HMN was about 10-fold greater than that of FNT. The t1/2 of both FNT and HMN was less than 5 min in the whole animal. Probenecid decreased the urinary excretion of HMN from 9.7 +/- 1.4% to 4.4 +/- 1.0% (p less than 0.05). Compared with HMN, FNT has less urinary excretion but a similar elimination t1/2, suggesting a greater nonrenal clearance. HMN but not FNT has tubular excretion. Thus, alterations in substituents of 5-nitrofurans markedly alter their renal handling and may partially explain their diverse toxic effects.
Ballal
S
S
Geriatric Research, Education and Clinical Center (GRECC), Veterans Administration Medical Center, St. Louis, MO 63125.
Spry
L A
LA
Zenser
T V
TV
Davis
B B
BB
D000818:Animals; D006827:Hydantoins / Q000378:metabolism* / Q000633:toxicity; D066298:In Vitro Techniques; D007444:Inulin; D007668:Kidney / Q000378:metabolism*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D009581:Nitrofurans / Q000378:metabolism* / Q000633:toxicity; D011339:Probenecid / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains
D006827:Hydantoins; D009581:Nitrofurans; C001252:nefurthiazole; D007444:Inulin; C008050:nifurmazole; D011339:Probenecid