新型抗炎镇痛剂SFZ-47在家兔体内羟基化及其结合型代谢产物的鉴定

目的：鉴定新型抗炎镇痛剂SFZ-47［3H-1,2-二氢-2-(4-甲基苯胺基)甲基-1-吡咯里嗪酮］在家兔体内的羟基化及其结合型代谢产物。方法：选择4只健康家兔单剂量口服100 mg SFZ-47，收集0～10 h的尿样。将未经或经过β-D-葡萄糖苷酸酶/硫酸酯酶水解的尿样以Sep-Pak C₁₈固相萃取柱纯化后，采用LC/MSn方法对尿中推测的代谢物分别进行选择离子监测(SIM)和多级全扫描质谱(MSⁿ)分析。结果：在尿中首次检测到SFZ-47羟基化及其β-D-葡糖苷酸与硫酸结合型代谢物。结论：SFZ-47在家兔体内主要代谢途径应为苯环上的甲基先氧化成羟甲基和羧基，再分别与β-D-葡糖醛酸或硫酸结合。

IDENTIFICATION OF HYDROXYLATED METABOLITE OF SFZ-47, A NOVEL ANTI-INFLAMMATORY AND ANALGESIC AGENT, AND ITS CONJUGATES IN RABBITS

AIM: To identify the metabolite of 3H-1,2-dihydro-2-(4-methyl-phenylamino) methyl-1-pyrrolizinone(SFZ-47), a novel anti-inflammatory and analgesic agent in rabbits. METHODS: Urine samples from 0 to 12 h were collected after single oral dose of 100 mg SFZ-47 to each of four rabbits. The urine samples with or without hydrolysis by β-glucuronidase/sulphatase were purified by SPE column (Sep-Pak C₁₈) and analyzed with LC/MSⁿ for potential metabolites. RESULTS: Hydroxylated metabolite of SFZ-47 and its conjugates of glucuronide and sulfate were first identified either by directly comparing the observed mass spectra and the chromatographic retention time with authentic substance or by the diagnostic ions in full scan MSⁿ (n=2,3) mode. CONCLUSION: According to the experimental results in this study, the major metabolic pathway of SFZ-47 in rabbits should be that the methyl group of SFZ-47 was oxidized to hydroxymethyl and then to carboxyl group, followed by conjugation with β-glucuronic acid or sulfuric acid.