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

作　　者：Yan LI Da-fang ZHONG Si-wei CHEN Isamu MAEBA 

机构地区：[1]School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China [2]School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China [3]Faculty of Pharmacy, Meijo University, Nagoya 460-8503, Japan

出　　处：《Acta Pharmacologica Sinica》2005年第12期1519-1526,共8页中国药理学报（英文版）

基　　金：Project supported by Grant 2003AA2Z347C of the 863 Program of China.

摘　　要：Aim： To identify 4 unknown metabolites of benproperine （BPE l） 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 ^1H and ^13C 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 rain imme- diately 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.Aim： To identify 4 unknown metabolites of benproperine （BPE l） 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 ^1H and ^13C 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 rain imme- diately 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.

关 键 词：BENPROPERINE METABOLISM antitussive agents HYDROXYLATION GLUCURONIDE high performance liquid chromatography mass spectrometry 

分 类 号：R974.2[医药卫生—药品]