Nagaraja N V, Singh S K, Paliwal J K, Gupta R C
Pharmacokinetics and Metabolism Division, Central Drug Research Institute, Lucknow, India.
J Pharm Pharmacol. 2000 Oct;52(10):1257-63. doi: 10.1211/0022357001777234.
Methyl-N[5 [[4-(2-pyridinyl)-1-piperazinyl]carbonyl]- 1H-benzimidazol-2-yl] carbamate (CDRI-81/470) is a broad spectrum anthelmintic agent, effective against both intestinal and systemic parasitism. Tissue distribution and excretion of CDR1-81/470 were studied in rats after a single oral dose of 100 mg kg(-1) CDRI-81/470. One of the metabolites was identified in pilot studies as its N-decarboxylate derivative and characterized by synthesis. HPLC assay methods for the simultaneous estimation of CDRI-81/470 and its N-decarboxylate derivative in tissues, bile, urine, and faeces were developed and validated. The parent compound was quantitated in all major tissues and organs up to 48 h post-dose. Among the tissues other than serum, the highest concentrations of CDRI-81/470 were found in liver, whereas only trace levels were found in brain. Approximately 3% of the administered dose was excreted unchanged in urine at 120 h postdose, whereas approximately 7% was recovered in faeces. The contribution of the biliary route for the excretion of parent compound was less than 0.5%. The N-decarboxylate derivative was quantitated in faeces (1-4%) and bile ( < 0.1%) but was absent in serum, tissues, and urine. An additional metabolite was isolated from bile and characterized as the pyridinyl-5-hydroxy derivative of CDRI-81/470. CDRI-81/470 showed rapid absorption and distribution into all major organs and tissues, and underwent extensive metabolism in rats. Two metabolites in bile were identified and characterized by synthesis.
甲基 - N[5 [[4 - (2 - 吡啶基)-1 - 哌嗪基]羰基]-1H - 苯并咪唑 - 2 - 基]氨基甲酸酯(CDRI - 81/470)是一种广谱驱虫剂，对肠道寄生虫和全身性寄生虫均有效。在大鼠单次口服100 mg kg(-1) CDRI - 81/470后，研究了CDR1 - 81/470的组织分布和排泄情况。在初步研究中，其中一种代谢产物被鉴定为其N - 脱羧衍生物，并通过合成进行了表征。建立并验证了用于同时测定组织、胆汁、尿液和粪便中CDRI - 81/470及其N - 脱羧衍生物的HPLC测定方法。给药后48小时内，母体化合物在所有主要组织和器官中均可定量。在血清以外的组织中，肝脏中CDRI - 81/470的浓度最高，而在脑中仅发现痕量水平。给药后120小时，约3%的给药剂量以原形从尿液中排泄，而约7%在粪便中回收。母体化合物经胆汁排泄的比例小于0.5%。N - 脱羧衍生物在粪便(1 - 4%)和胆汁(<0.1%)中可定量，但在血清、组织和尿液中不存在。从胆汁中分离出另一种代谢产物，并鉴定为CDRI - 81/470的吡啶基 - 5 - 羟基衍生物。CDRI - 81/470显示出快速吸收并分布到所有主要器官和组织中，并在大鼠体内经历了广泛的代谢。通过合成鉴定并表征了胆汁中的两种代谢产物。
