Nomeir A A, Markham P, Burka L T, Griffin R J, Ghanayem B I
Arthur D. Little, Inc. Cambridge, Massachusetts, USA.
J Pharmacol Exp Ther. 1996 Oct;279(1):222-30.
Nalidixic acid (NA) is an antimicrobial drug that has been used to treat urinary tract infections. A study of NA by the National Toxicology Program indicated that chronic administration in the diet at doses equivalent to 82 and 175 mg/kg/day for rats, and 175 and 475 mg/kg/day for mice resulted in neoplastic lesions in the preputial and clitoral glands of male and female Fischer 344 rats, respectively, but not in male and female B6C3F1 mice. Our study was designed to evaluate the metabolic basis of this species and tissue-dependent carcinogenicity. [14C]NA was administered by oral gavage as a suspension in corn oil at doses 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 excreted primarily in urine and feces. The urinary and fecal metabolite profiles were species dependent. At 72 hr after administration, in both genders of rats and mice, the highest concentrations of radioactivity were observed in the liver, and the lowest were in the brain and adipose tissue. The preputial and clitoral glands of male and female rats, respectively, contained consistently and substantially higher concentrations of radioactivity compared to all other tissues, with the exception 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 differences in carcinogenicity of NA were associated with differences in metabolism and disposition between the two species.
萘啶酸（NA）是一种用于治疗尿路感染的抗菌药物。美国国家毒理学计划对NA的一项研究表明，以相当于82和175毫克/千克/天的剂量长期喂食大鼠，以及以175和475毫克/千克/天的剂量长期喂食小鼠，分别导致雄性和雌性Fischer 344大鼠的包皮腺和阴蒂腺出现肿瘤性病变，但在雄性和雌性B6C3F1小鼠中未出现。我们的研究旨在评估这种物种和组织依赖性致癌性的代谢基础。[14C]NA以玉米油悬浮液的形式通过口服灌胃给药，剂量为20、200或500毫克/千克。根据尿液排泄数据，小鼠和大鼠胃肠道分别吸收了至少35%至46%和57%至79%的剂量。NA衍生的放射性主要通过尿液和粪便排出。尿液和粪便中的代谢物谱具有物种依赖性。给药后72小时，在大鼠和小鼠的两性中，肝脏中的放射性浓度最高，而大脑和脂肪组织中的放射性浓度最低。雄性和雌性大鼠的包皮腺和阴蒂腺分别始终含有比所有其他组织（肝脏除外）高得多的放射性浓度。在小鼠中，这些组织中的放射性水平接近或低于可量化水平。在20至500毫克/千克的剂量范围内，NA在雄性和雌性小鼠中的代谢和处置特征呈线性：在大鼠中，它们具有剂量依赖性。这项研究的结果表明，NA致癌性的物种和组织依赖性差异与这两个物种之间的代谢和处置差异有关。
