Departments of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, USA.
Drug Metab Dispos. 2010 Nov;38(11):2049-59. doi: 10.1124/dmd.110.034850. Epub 2010 Jul 28.
(3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)-3-piperidinol (BMS-690514), an oral selective inhibitor of human epidermal growth factor receptors 1 (or epidermal growth factor receptor), 2, and 4, and vascular endothelial growth factor receptors 1, 2, and 3, is being developed as a treatment for patients with non-small-cell lung cancer and metastatic breast cancer. The disposition of [(14)C]BMS-690514 was investigated in nine healthy male subjects (group 1, n = 6; group 2, n = 3) after oral administration of a 200-mg dose. Urine, feces, and plasma were collected from all subjects for up to 12 days postdose. In group 2 subjects, bile was collected from 3 to 8 h postdose. Across groups, approximately 50 and 34% of administered radioactivity was recovered in the feces and urine, respectively. An additional 16% was recovered in the bile of group 2 subjects. Less than 28% of the dose was recovered as parent drug in the combined excreta, suggesting that BMS-690514 was highly metabolized. BMS-690514 was rapidly absorbed (median time of maximum observed concentration 0.5 h) with the absorbed fraction estimated to be approximately 50 to 68%. BMS-690514 represented ≤7.9% of the area under the concentration-time curve from time 0 extrapolated to infinite time of plasma radioactivity, indicating that the majority of the circulating radioactivity was from metabolites. BMS-690514 was metabolized via multiple oxidation reactions and direct glucuronidation. Circulating metabolites included a hydroxylated rearrangement product (M1), a direct ether glucuronide (M6), and multiple secondary glucuronide conjugates. None of these metabolites is expected to contribute to the pharmacology of BMS-690514. In summary, BMS-690514 was well absorbed and extensively metabolized via multiple metabolic pathways in humans, with excretion of drug-related radioactivity in both bile and urine.
（3R,4R）-4-氨基-1-((4-((3-甲氧基苯基)氨基)吡咯并[2,1-f][1,2,4]三嗪-5-基)甲基)-3-哌啶醇（BMS-690514）是一种口服选择性人表皮生长因子受体 1（或表皮生长因子受体）、2 和 4，以及血管内皮生长因子受体 1、2 和 3 的抑制剂，正在开发用于治疗非小细胞肺癌和转移性乳腺癌患者。在九名健康男性受试者（第 1 组，n = 6；第 2 组，n = 3）中口服 200mg 剂量后，研究了[14C]BMS-690514 的处置情况。所有受试者在给药后 12 天内收集尿液、粪便和血浆。在第 2 组受试者中，从给药后 3 至 8 小时收集胆汁。在各组中，约 50%和 34%的放射性物质分别在粪便和尿液中回收。在第 2 组受试者的胆汁中回收了另外 16%。在组合排泄物中，不到 28%的剂量以母体药物回收，表明 BMS-690514 高度代谢。BMS-690514 吸收迅速（最大观察浓度的中位时间为 0.5 小时），估计吸收部分约为 50%至 68%。BMS-690514 代表从时间 0 外推至血浆放射性无限时间的浓度-时间曲线下面积的≤7.9%，表明循环放射性的大部分来自代谢物。BMS-690514 通过多种氧化反应和直接葡萄糖醛酸化代谢。循环代谢产物包括羟化重排产物（M1）、直接醚葡萄糖醛酸化物（M6）和多种次级葡萄糖醛酸缀合物。这些代谢物均预计不会对 BMS-690514 的药理学产生影响。总之，BMS-690514 在人体内通过多种代谢途径被很好地吸收并广泛代谢，药物相关放射性物质从胆汁和尿液中排泄。
