Flavin-containing monooxygenase (FMO) catalyzes the oxygenation of a wide variety of medicines and dietary-derived compounds. However, little information is available regarding drug interactions mediated by FMO3 in vivo. Consequently, we investigated interactions between FMO substrates in humanized-liver mice. Trimethylamine-d9 and itopride were, respectively, intravenously and orally administered to humanized-liver mice (n = 5-7). The pharmacokinetic profiles of itopride (the victim drug) in the presence of trimethylamine (the perpetrator drug) were determined for 24 h after co-administration using liquid chromatography/tandem mass spectrometry. Itopride (10 mg/kg) was extensively oxygenated in humanized-liver mice to its N-oxide. The plasma concentrations of itopride N-oxide after co-administration of itopride and trimethylamine (10 and 100 mg/kg) were significantly suppressed in a dose-dependent manner, but only during the early phase, i.e., up to 2 h after co-administration. With the higher dose of trimethylamine, the areas under the concentration-time curves of itopride and its N-oxide significantly increased (1.6-fold) and decreased (to 60%), respectively; modeling suggested that these modified pharmacokinetics resulted from suppression of the in vivo hepatic intrinsic clearance (to 67%). These results suggest that food-derived trimethylamine may result in interactions with FMO drug substrates immediately after administration; however, the potential for this to occur in vivo may be limited.

译文

:含黄素的单加氧酶(FMO)催化多种药物和膳食衍生化合物的氧化。但是,关于FMO3在体内的药物相互作用的信息很少。因此,我们调查了人源化肝脏小鼠中FMO底物之间的相互作用。将三甲胺-d9和伊托必利分别静脉内和口服给予人源化肝小鼠(n = 5-7)。在液相色谱/串联质谱联用后24小时内,确定在三甲胺(作恶药)存在下伊托必利(受害药)的药代动力学概况。依托必利(10 mg / kg)在人源化肝小鼠中被广泛氧化成其N-氧化物。依托必利和三甲胺并用后血浆中的依托必利N-氧化物的血浆浓度(10和100 mg / kg)以剂量依赖的方式被显着抑制,但仅在早期阶段,即在合用后直至2小时行政。随着三甲胺剂量的增加,伊托必利及其氮氧化物的浓度-时间曲线下的面积分别显着增加(1.6倍)和减少(至60%)。模型表明这些修饰的药代动力学是由体内肝内在清除率的抑制(至67%)导致的。这些结果表明,食品中的三甲胺可能会在给药后立即与FMO药物底物发生相互作用。但是,这种可能性在体内可能会受到限制。

+1
+2
100研值 100研值 ¥99课程
检索文献一次
下载文献一次

去下载>

成功解锁2个技能,为你点赞

《SCI写作十大必备语法》
解决你的SCI语法难题!

技能熟练度+1

视频课《玩转文献检索》
让你成为检索达人!

恭喜完成新手挑战

手机微信扫一扫,添加好友领取

免费领《Endnote文献管理工具+教程》

微信扫码, 免费领取

手机登录

获取验证码
登录