Drug Disposition/Pharmacokinetics/Pharmacodynamics, Lilly Research Laboratories,Indianapolis, Indiana, USA.
Drug Metab Dispos. 2013 Apr;41(4):714-26. doi: 10.1124/dmd.112.048488. Epub 2013 Jan 10.
LY2090314 (3-[9-fluoro-2-(piperidin-1-ylcarbonyl)-1,2,3,4-tetrahydro[1,4]diazepino[6,7,1-hi]indol-7-yl]-4-imidazo[1,2-a]pyridin-3-yl-1H-pyrrole-2,5-dione) is an intravenous glycogen synthase kinase-3 inhibitor in oncology trials. Drug disposition was characterized after intravenous infusion of [(14)C]LY2090314 to rats and dogs, and was related to available clinical data. LY2090314 exhibited high clearance (approximating hepatic blood flow) and a moderate volume of distribution (∼1-2 l/kg) resulting in rapid elimination (half-life ∼0.4, 0.7, and 1.8-3.4 hours in rats, dogs, and humans, respectively). Scaled clearance from liver microsomes accurately predicted perfusion-limited clearance across species. LY2090314 was cleared by extensive metabolism, and the numerous metabolites were rapidly excreted into feces via bile (69-97% of dose; 62-93% within 0-24 hours); urinary recovery of drug-related material was low (≤3% of dose). Despite extensive metabolism, in rats and humans the parent compound was the sole identifiable drug-related moiety in plasma. Even in Mdr1a-, Bcrp-, and Mrp2-knockout rats, LY2090314 metabolites did not appear in circulation, and their urinary excretion was not enhanced, because the hypothesized impaired biliary excretion of metabolites in the absence of these canalicular transporters was not observed. Canine metabolite disposition was generally similar, with the notable exception of dog-unique LY2090314 glucuronide. This conjugate was formed in the dog liver and was preferentially excreted into the blood, where it accounted for the majority of circulating radioactivity at later times, and was predominantly recovered in urine (16% of dose). In conclusion, LY2090314 was rapidly cleared by extensive metabolism with negligible circulating metabolite exposures due to biliary excretion of metabolites into feces with no apparent intestinal reabsorption.
LY2090314（3-[9-氟-2-（哌啶-1-羰基）-1,2,3,4-四氢[1,4]二氮杂卓[6,7,1-hi]吲哚-7-基]-4-咪唑[1,2-a]吡啶-3-基-1H-吡咯-2,5-二酮）是一种在肿瘤试验中的静脉注射糖原合酶激酶-3 抑制剂。在大鼠和犬中静脉输注[14C]LY2090314 后，对其药物分布进行了特征描述，并与可用的临床数据相关。LY2090314 表现出高清除率（接近肝血流量）和中等分布容积（约 1-2 l/kg），导致快速消除（半衰期分别为 0.4、0.7 和 1.8-3.4 小时，在大鼠、犬和人中）。从肝微粒体中推算出的清除率准确地预测了种间灌注受限的清除率。LY2090314 被广泛代谢清除，许多代谢物通过胆汁迅速排泄到粪便中（69-97%的剂量；62-93%在 0-24 小时内）；药物相关物质在尿中的回收率较低（≤3%的剂量）。尽管存在广泛的代谢，但在大鼠和人中，母体化合物是血浆中唯一可识别的药物相关部分。即使在 Mdr1a-、Bcrp-和 Mrp2 敲除大鼠中，LY2090314 代谢物也未出现在循环中，其尿排泄也未增加，因为在不存在这些管腔转运蛋白的情况下，假设代谢物的胆汁排泄受损并未观察到。犬类代谢物的处置通常相似，唯一的例外是犬类特有的 LY2090314 葡萄糖醛酸苷。这种结合物在狗的肝脏中形成，并优先排泄到血液中，在后期，它在血液中占循环放射性的大部分，并主要在尿液中回收（剂量的 16%）。总之，由于代谢物通过胆汁排泄到粪便中，没有明显的肠道重吸收，因此 LY2090314 被广泛代谢迅速清除，循环代谢物暴露量可忽略不计。
