四氢氨基吖啶衍生物（SM-10888）在大鼠体内的代谢：通过快原子轰击串联质谱法对SM-10888的N-葡萄糖醛酸苷和羟基化SM-10888的O-葡萄糖醛酸苷进行结构分析。

Metabolism of a tetrahydroaminoacridine derivative (SM-10888) in rat: structural analysis of an N-glucuronide of SM-10888 and an O-glucuronide of hydroxylated SM-10888 by FAB-MS/MS.

Yabuki M, Mine T, Iba K, Nakatsuka I, Yoshitake A

Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd, Osaka, Japan.

Xenobiotica. 1993 Dec;23(12):1367-75. doi: 10.3109/00498259309059446.

Abstract

The metabolism of 9-amino-8-fluoro-1,2,3,4-tetrahydro-2,4-methanoacridine citrate (SM-10888), a cholinesterase inhibitor was studied in rat. 2. The phase I metabolite (designated M3) was isolated from urine and identified as 1-hydroxylated SM-10888 by 1H-n.m.r. and EI-MS. 3. Two glucuronides (designated SMG and M3G) were isolated from bile and urine and their structures examined by FAB-MS/MS and beta-glucuronidase hydrolysis. 4. FAB-mass spectra of SMG and M3G showed molecular ions ([M+H]+) at m/z 405 and 421, respectively. In their daughter spectra, fragment ions of aglycones (SM-10888 and M3), generated by the loss of glucuronic acid (176 amu) were observed. The daughter spectra of these aglycones were essentially similar to those of the corresponding synthetic standards. 5. SMG was hydrolysed non-enzymically at pH 5 as is often the case with N-glucuronides of arylamines. M3G could be hydrolysed by beta-glucuronidase but proved stable at pH 5. 6. From these results, SMG and M3G were concluded to be the N-glucuronide of SM-10888 and the O-glucuronide of M3, respectively.

摘要

在大鼠体内研究了胆碱酯酶抑制剂9-氨基-8-氟-1,2,3,4-四氢-2,4-亚甲基吖啶柠檬酸盐（SM-10888）的代谢情况。2. 从尿液中分离出I相代谢物（命名为M3），并通过1H-核磁共振和电子轰击质谱鉴定为1-羟基化的SM-10888。3. 从胆汁和尿液中分离出两种葡糖醛酸苷（命名为SMG和M3G），并通过快原子轰击串联质谱和β-葡糖醛酸酶水解研究它们的结构。4. SMG和M3G的快原子轰击质谱显示分子离子（[M+H]+）分别在m/z 405和421处。在它们的子谱中，观察到因葡糖醛酸（176原子质量单位）丢失而产生的苷元（SM-10888和M3）的碎片离子。这些苷元的子谱与相应合成标准品的子谱基本相似。5. SMG在pH 5时非酶促水解，芳胺的N-葡糖醛酸苷通常如此。M3G可被β-葡糖醛酸酶水解，但在pH 5时稳定。6. 根据这些结果，得出结论：SMG和M3G分别是SM-10888的N-葡糖醛酸苷和M3的O-葡糖醛酸苷。