Department of Drug Metabolism, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
Drug Metab Dispos. 2010 Apr;38(4):667-78. doi: 10.1124/dmd.109.031476. Epub 2010 Jan 19.
The pharmacokinetics and metabolism of linagliptin (BI1356, 8-(3R-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione) were investigated in healthy volunteers. The 10- and 5-mg (14)C-labeled drug was administered orally or intravenously, respectively. Fecal excretion was the dominant excretion pathway with 84.7% (p.o.) and 58.2% (i.v.) of the dose. Renal excretion accounted for 5.4% (p.o.) and 30.8% (i.v.) of the dose. Unchanged linagliptin was the most abundant radioactive species in all matrices investigated. The exposure (area under the curve 0-24 h) to the parent compound in plasma accounted for 191 nM . h (p.o.) and 356 nM . h (i.v.), respectively. The main metabolite 7-but-2-ynyl-8-(3S-hydroxy-piperidin-1-yl)-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (CD1790) was observed with >10% of parent compound systemic exposure after oral administration. The metabolite was identified as S-3-hydroxypiperidinly derivative of linagliptin. Experiments that included stable-labeled isotope techniques indicated that CD1790 was formed by a two-step mechanism via the ketone 7-but-2-yn-1-yl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-8-(3-oxopiperidin-1-yl)-3,7-dihydro-1H-purine-2,6-dione (CD10604). The initial ketone formation was CYP3A4-dependent and rate-limiting for the overall reaction to CD1790. Aldo-keto reductases with minor contribution of carbonyl reductases were involved in the subsequent stereoselective reduction of CD10604 to CD1790. The antipodes of linagliptin and CD1790 were not observed with adequate enantioselective liquid chromatography-tandem mass spectrometry methods. Other minor metabolites were identified by mass spectrometry and NMR investigations. However, it was concluded that the metabolites of linagliptin only play a minor role in the overall disposition and elimination of linagliptin.
在健康志愿者中研究了利拉利汀（BI1356，8-（3R-氨基-哌啶-1-基）-7-丁炔基-3-甲基-1-（4-甲基-喹唑啉-2-基甲基）-3,7-二氢-嘌呤-2,6-二酮）的药代动力学和代谢。分别口服和静脉内给予 10 和 5mg 的[14C]标记药物。粪便排泄是主要的排泄途径，剂量分别为 84.7%（po）和 58.2%（iv）。肾脏排泄分别占剂量的 5.4%（po）和 30.8%（iv）。未改变的利拉利汀是所有研究基质中最丰富的放射性物质。血浆中原药的暴露量（0-24 小时的曲线下面积）分别占 191 nM. h（po）和 356 nM. h（iv）。主要代谢物 7-丁炔基-8-（3S-羟基-哌啶-1-基）-3-甲基-1-（4-甲基-喹唑啉-2-基甲基）-3,7-二氢-嘌呤-2,6-二酮（CD1790）在口服给药后观察到超过母体化合物全身暴露的 10%。该代谢物被鉴定为利拉利汀的 S-3-羟基哌啶衍生物。包括稳定标记同位素技术的实验表明，CD1790 通过两步机制形成，通过酮 7-丁炔基-1-基-3-甲基-1-[(4-甲基喹唑啉-2-基)甲基]-8-(3-氧代哌啶-1-基)-3,7-二氢-1H-嘌呤-2,6-二酮（CD10604）。酮的初始形成是由 CYP3A4 依赖性和限速的，对于整体反应到 CD1790。醛酮还原酶在 CD10604 到 CD1790 的后续立体选择性还原中起次要作用。利拉利汀和 CD1790 的对映异构体没有用足够的对映选择性液相色谱-串联质谱方法观察到。通过质谱和 NMR 研究鉴定了其他少量代谢物。然而，结论是利拉利汀的代谢物仅在利拉利汀的整体处置和消除中起次要作用。
