SPECIES-DIFFERENCES IN THE DISPOSITION AND METABOLISM OF NALIDIXIC-ACID

Nalidixic acid (NA) is an antimicrobial drug that has been used to tre at urinary tract infections. A study of NA by the National Toxicology Program indicated that chronic administration in the diet at doses equ ivalent to 82 and 175 mg/kg/day for rats, and 175 and 475 mg/kg/day fo r mice resulted in neoplastic lesions in the preputial and clitoral gl ands of male and female Fischer 344 rats, respectively, but not in mal e and female B6C3F1 mice. Our study was designed to evaluate the metab olic basis of this species and tissue-dependent carcinogenicity. [C-14 ]NA was administered by oral gavage as a suspension in corn oil at dos es of 20, 200 or 500 mg/kg. Based on urinary excretion data, at least 35 to 46 and 57 to 79% of dose was absorbed from the gastrointestinal tracts of mice and rats, respectively. NA-derived radioactivity was ex creted primarily in urine and feces. The urinary and fecal metabolite profiles were species dependent. At 72 hr after administration, in bot h genders of rats and mice, the highest concentrations of radioactivit y were observed in the liver, and the lowest were in the brain and adi pose tissue. The preputial and clitoral glands of male and female rats , respectively, contained consistently and substantially higher concen trations of radioactivity compared to all other tissues, with the exce ption of liver. In mice, the levels of radioactivity in these tissues were near or below quantifiable levels. The metabolism and disposition characteristics of NA were linear in male and female mice over a dose range of 20 to 500 mg/kg; in rats, they were dose dependent. Results of this study suggest that the species- and tissue-dependent differenc es in carcinogenicity of NA were associated with differences in metabo lism and disposition between the two species.