Identification of some benproperine metabolites in humans and investigation of their antitussive effect

被引:6
作者
Li, Y
Zhong, DF [1 ]
Chen, SW
Maeba, I
机构
[1] Shenyang Pharmaceut Univ, Sch Pharm, Shenyang 110016, Peoples R China
[2] Shenyang Pharmaceut Univ, Sch Pharmaceut Engn, Shenyang 110016, Peoples R China
[3] Meijo Univ, Fac Pharm, Nagoya, Aichi 4608503, Japan
关键词
benproperine; metabolism; antitussive agents; hydroxylation; glucuronide; high performance liquid chromatography; mass spectrometry;
D O I
10.1111/j.1745-7254.2005.00212.x
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Aim: To identify 4 unknown metabolites of benproperine (BPP, 1) in human urine after a po dose, and to investigate the antitussive effect of monohydroxylate metabolites. Methods: The putative metabolite references were prepared using chemical synthesis. Their structures were identified using H-1 and C-13 nuclear magnetic resonance, and mass spectrometry. The metabolites in human urine were separated and assayed using liquid chromatography-ion trap mass spectrometry (LC/MS/MS), and further confirmed by comparison of their mass spectra and chromatographic retention times with those of synthesized reference substances. The antitussive effects of metabolites were evaluated on coughs induced by 7.5% citric acid in conscious guinea pigs. Results: 1-[1-Methyl-2-[2-(phenylmethyl)phenoxy]-ethyl]-4-piperidinol (2), 1-[1-methyl-2-[2-(phenylmethyl) phenoxy] ethyl]-3-piperidinol (3) and their glucuronides 4 and 5 were obtained from chemical synthesis. Four urinary metabolites in human urine showed peaks with the same chromatographic retention times and mass spectra in LC/MS/MS as synthetic substances 2, 3, 4 and 5. Phosphates of compounds 2 and 3 prolonged the latency of cough and reduced the number of coughs during the 3 min test using citric acid, but did not reduce the number of coughs during the 5 min immediately after the test in conscious guinea pigs. Conclusion: Compounds 2, 3, 4, and 5 were identified as the metabolites of BPP in human urine. Among them, compounds 2 and 3 are inactive in the antitussive effect.
引用
收藏
页码:1519 / 1526
页数:8
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