Nakada Naoyuki
Analysis and Pharmacokinetics Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Miyukigaoka 21, Tsukuba, Ibaraki, 305-8585, Japan.
Drugs R D. 2016 Jun;16(2):205-16. doi: 10.1007/s40268-016-0130-3.
YM758 monophosphate is a novel If channel inhibitor that has an inhibitory action for If current and shows a strong and specific activity, selectively lowering the heart rate and decreasing oxygen consumption by heart muscle.
The objectives of the current study were to investigate the in vivo metabolic profiles of YM758 in mice, rats, rabbits, dogs, and monkeys and to elucidate the structures of YM758 metabolites.
Biological samples were analyzed by liquid chromatography hyphenated with a radiometric detection system and liquid chromatography coupled with a mass spectrometer to clarify their metabolic patterns. To elucidate their structures, metabolites were isolated and analyzed by mass spectrometry and nuclear magnetic resonance spectroscopy.
Our results from in vivo metabolic profiling in humans and animals indicated there is no significant species difference in the metabolism of YM758, and the metabolic pathways of YM758 are considered to be oxidation, hydration, and demethylation followed by sulfate or glucuronide conjugation.
YM758单磷酸盐是一种新型的If通道抑制剂，对If电流具有抑制作用，表现出强大且特异的活性，可选择性降低心率并减少心肌耗氧量。
本研究的目的是研究YM758在小鼠、大鼠、兔子、狗和猴子体内的代谢概况，并阐明YM758代谢产物的结构。
通过液相色谱与放射性检测系统联用以及液相色谱与质谱联用对生物样品进行分析，以阐明其代谢模式。为了阐明其结构，对代谢产物进行分离，并通过质谱和核磁共振光谱进行分析。
我们在人和动物体内代谢概况研究的结果表明，YM758的代谢在物种间无显著差异，YM758的代谢途径被认为是氧化、水化、去甲基化，随后是硫酸盐或葡萄糖醛酸结合。
