In vitro metabolism of TJ0711,a novel vasodilatory β-blocker,in mouse,rat,dog,and human liver microsomes
1-”4-(2-methoxyethyl)-phenoxy”-3-”2-(2-methoxyphenoxy)-ethylamino”-2-propanol (TJ0711), is a novel β-adrenoreceptor blocker with vasodilating activity.The aim of this study was to investigate the in vitro metabolic profiles of T J0711 from both qualitative and quantitative aspects, in terms of metabolite identification, metabolic stability, the potential species differences and gender effect, using liver microsomes (LM) from mouse, rat, dog and human of different genders.To help characterize the metabolic properties of TJ0711, two major metabolites were synthesized and incubated in parallel.In vitro-in vivo extrapolation and allometric scaling were also performed.21 phase I metabolites including twelve previously unreported metabolites have been detected, and these structures were elucidated by liquid chromatographic-tandem mass spectrometry (LC-MS/MS).TJ0711 was rapidly metabolized in liver microsomes from both genders of all four species, and the metabolism of TJ0711 was more complicated in rodents than in non-rodents.No unique human metabolite was observed and metabolite profiles between males and females for the same species were similar.Oxidation was the predominant pathway for all the four species.The fastest metabolite rate of TJ0711 was observed in mouse, with in vivo intrinsic clearance (CL”) values of 472.5 and 661.5 ml/min/kg for the males and females, followed by rat, dog and humans.According to allometric scaling method, good correlations (R2□□0.98) were observed between predicted hepatic clearance (CLH) values and body weights (BW) for T J0711, but poor for M1 (R2=0.30 for males, 0.33 for females).The dog was the species that showed most similar metabolic behavior to that of humans, qualitatively and quantitatively.The valuable information provided in this work will be useful in planning and interpreting further pharmacokinetic, in vivo metabolism and toxicological studies of this novel β-blocker.
TJ0711 Metabolism Liver microsomes Mass spectrometry
Lei Hu Xiaolong Xu Peng Cao Jiangeng Huang Luqin Si Gao Li
Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China
国内会议
2013年中国药物制剂大会——中国药学会药剂专业委员会2013年学术年会暨国际控释协会中国分会2013年学术年会
武汉
英文
432-434
2013-10-26（万方平台首次上网日期，不代表论文的发表时间）