Timchalk C, Dryzga M D, Johnson K A, Eddy S L, Freshour N L, Kropscott B E, Nolan R J
Dow Chemical Company, Midland, MI 48674, USA.
J Appl Toxicol. 1997 Jan-Feb;17(1):9-21. doi: 10.1002/(sici)1099-1263(199701)17:1<9::aid-jat390>3.0.co;2-s.
This study was conducted to provide data on the pharmacokinetics of [14C]metosulam (N-[2,6-dichloro-3-methylphenyl]-5,7-dimethoxy-1,2,4-triazolo-[1,5a]- pyrimidine-2-sulfonamide). Groups of male Sprague-Dawley rats, CD-1 mice and Beagle dogs were given a single oral gavage dose of 100 mg [14C]metosulam kg-1 body weight and blood, urine, feces and selected tissue specimens were collected up to 168 h for rats and mice and 216 h post-dosing for dogs. Two of these dogs received a second oral dose of 100 mg kg-1 and were humanely euthanized at 12 h post-dosing and selected tissues were collected. The third dog was administered an intravenous dose of 1 mg kg-1 and plasma, urine and feces were collected for 72 h post-dosing. Specified tissue specimens were analyzed for 14C activity and selected tissues were evaluated for localization of 14C activity by histoautoradiography. Selected urine and plasma specimens were also profiled for metabolites by high-performance liquid chromatography. [14C]Metosulam was absorbed rapidly (t1/2 < 1 h) in all three species. Mice and dogs absorbed ca. 20% of the orally administered dose of [14C]metosulam, compared to > 70% absorption in the rat. Analysis of 14C activity and histoautoradiography of the dog eyes indicated that the retina, a target for toxicity in the dog, did exhibit affinity for the radiotracer. There was no evidence of 14C localization in the kidneys of dogs or in the eyes of rats. In rats and mice the 14C plasma time-course was fit to a two-compartment pharmacokinetic model, whereas the dog was fit to a one-compartment model. The half-lives for the rapid initial (alpha) and slower terminal phases (beta) were 9 h and 60 h for the rat and 20 h and 155 h for mice, respectively. The dog had an elimination t1/2 of 73 h. In all three species, [14C]metosulam and metabolites were excreted in the urine and quantitatively the relative amount of [14C]metosulam metabolism followed the pattern of mice > rats > dogs. These data suggest that the observed ocular lesion in dogs is due to metosulam and may in part be due to its selective affinity for the dog retina.
本研究旨在提供[14C]甲磺胺磺隆（N-[2,6-二氯-3-甲基苯基]-5,7-二甲氧基-1,2,4-三唑并-[1,5a]-嘧啶-2-磺酰胺）的药代动力学数据。将雄性Sprague-Dawley大鼠、CD-1小鼠和比格犬分组，单次经口灌胃给予100 mg [14C]甲磺胺磺隆/千克体重，并在给药后长达168小时收集大鼠和小鼠的血液、尿液、粪便及选定的组织标本，给药后216小时收集犬的上述样本。其中两只犬接受第二次经口给药，剂量为100 mg/千克，并在给药后12小时实施安乐死并收集选定组织。第三只犬静脉注射1 mg/千克剂量，并在给药后72小时收集血浆、尿液和粪便。分析特定组织标本的14C活性，并通过组织放射自显影评估选定组织中14C活性的定位。还通过高效液相色谱对选定的尿液和血浆标本进行代谢物分析。[14C]甲磺胺磺隆在所有三个物种中均迅速吸收（t1/2 < 1小时）。小鼠和犬吸收约20%经口给予的[14C]甲磺胺磺隆剂量，而大鼠的吸收量> 70%。对犬眼的14C活性分析和组织放射自显影表明，作为犬中毒靶标的视网膜对放射性示踪剂确实具有亲和力。没有证据表明14C在犬肾或大鼠眼中定位。在大鼠和小鼠中，14C血浆时间过程符合二室药代动力学模型，而犬符合一室模型。大鼠快速初始（α）和较慢终末相（β）的半衰期分别为9小时和60小时，小鼠分别为20小时和155小时。犬的消除t1/2为73小时。在所有三个物种中，[14C]甲磺胺磺隆及其代谢物均经尿液排泄，并且从数量上看，[14C]甲磺胺磺隆代谢的相对量遵循小鼠>大鼠>犬的模式。这些数据表明，在犬中观察到的眼部病变是由甲磺胺磺隆引起的，并且可能部分归因于其对犬视网膜的选择性亲和力。
