Tracy J W, Webster L T
J Pharmacol Exp Ther. 1981 May;217(2):363-8.
This study was designed to identify the site of formation of 1-thiocarbamoyl-2-imidazolidinone (TCI), a potent immunoactive metabolite of the antihelminthic drug, niridazole. When niridazole was administered intragastrically to C57Bl/6J mice, a 4-hr delay was observed before TCI was detected in the serum. By contrast, 4-hydroxyniridazole, a marker of hepatic niridazole metabolism, appeared in the serum within 30 min. Changing the route of niridazole administration from intragastric to intracaecal abolished the lag period in the rise of serum TCI concentrations relative to the 4-hydroxyniridazole marker. Pretreatment of mice with neomycin sulfate reduced the amount of TCI excreted in the urine by about 90% over a 24-hr period, but did not affect the amount of 4-hydroxyniridazole excreted. Injection of niridazole into isolated segments of mouse intestine resulted in TCI production, with the greatest conversion noted in the caecum. Subsequent incubation of niridazole with suspensions of mouse caecum contents in vitro also resulted in the formation of TCI, but not 4-hydroxyniridazole. Attempts to demonstrate TCI formation in vitro with various fractions of mouse liver were unsuccessful. These results indicate a dissociation of TCI formation from the major hepatic pathway of niridazole metabolism and support the view that TCI is formed from niridazole in the gastrointestinal tract as a result of the action of intestinal microflora.
本研究旨在确定抗蠕虫药硝唑咪的一种强效免疫活性代谢物1-硫代氨基甲酰基-2-咪唑烷酮（TCI）的形成部位。当向C57Bl/6J小鼠胃内给予硝唑咪时，在血清中检测到TCI之前观察到4小时的延迟。相比之下，肝内硝唑咪代谢标志物4-羟基硝唑咪在30分钟内出现在血清中。将硝唑咪的给药途径从胃内给药改为盲肠内给药，消除了血清TCI浓度相对于4-羟基硝唑咪标志物升高的延迟期。用硫酸新霉素预处理小鼠可使24小时内尿中排出的TCI量减少约90%，但不影响4-羟基硝唑咪的排出量。将硝唑咪注入小鼠离体肠段可产生TCI，在盲肠中转化率最高。随后在体外将硝唑咪与小鼠盲肠内容物悬液孵育也导致TCI的形成，但未形成4-羟基硝唑咪。用小鼠肝脏的各种组分在体外证明TCI形成的尝试均未成功。这些结果表明TCI的形成与硝唑咪代谢的主要肝途径分离，并支持TCI是由于肠道微生物群的作用在胃肠道中由硝唑咪形成的观点。
