Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA 94080, USA.
Drug Metab Dispos. 2013 Feb;41(2):508-17. doi: 10.1124/dmd.112.047019. Epub 2012 Dec 4.
The compound (S)-1-[(S)-2-cyclohexyl-2-([S]-2-[methylamino]propanamido)acetyl]-N-(4-phenyl-1,2,3-thiadiazol-5-yl)pyrrolidine-2-carboxamide (GDC-0152) is a peptidomimetic small molecule antagonist of inhibitor of apoptosis (IAP) proteins with antitumor activity. The mass balance, pharmacokinetics, tissue distribution and metabolism of GDC-0152 was investigated in rats following intravenous administration of 15 mg/kg of [(14)C]GDC-0152, labeled either at the terminal phenyl ring (A) or at the carbonyl of the 2-amino-2-cyclohexylacetyl moiety (B). In rats, 92.2%-95.1% of the radiolabeled GDC-0152 dose was recovered. Approximately 62.3% and 25.1% of A was excreted in urine and feces, respectively. By contrast, B was excreted almost equally in urine (27.2%), feces (32.2%), and expired air (27.5%). GDC-0152 underwent extensive metabolism, with less than 9% of the dose recovered as parent in excreta. Similarly, in plasma, GDC-0152 represented 16.7% and 7.5% of the area under the curve of the total radioactivity for A and B, respectively. The terminal half-life (t(1/2)) for total radioactivity was longer for B (21.2 hours) than for A (4.59 hours). GDC-0152 was highly metabolized via oxidation and amide hydrolysis, followed by subsequent sulfation and glucuronidation. The most abundant circulating metabolites were the amide hydrolyzed products, M26, M28, M30, M31, and M34, which ranged from 3.5% to 9.0% of total radioactivity. In quantitative whole-body autoradiography studies, the residence of radioactivity in tissues was longer for B than for A, which is consistent with the t(1/2) of the total radioactivity in circulation. A novel 4-phenyl-5-amino-1,2,3-thiadiazole (M28) oxidative cleavage resulted in the formation of hippuric acid (M24). This biotransformation was also observed in rat hepatocyte incubations with para-substituted M28 analogs. In addition, the formation of M24 was inhibited by 1-aminobenzotriazole, which points to the involvement of P450 enzymes.
化合物（S）-1-[(S)-2-环己基-2-[[S]-2-[甲基氨基]丙酰胺基]乙酰基]-N-（4-苯基-1,2,3-噻二唑-5-基）吡咯烷-2-甲酰胺（GDC-0152）是一种具有抗肿瘤活性的凋亡抑制因子（IAP）蛋白的肽模拟小分子拮抗剂。在大鼠体内静脉注射 15mg/kg 的[14C]GDC-0152 后，研究了 GDC-0152 的质量平衡、药代动力学、组织分布和代谢情况，[14C]GDC-0152 标记在末端苯基环（A）或 2-氨基-2-环己基乙酰基部分的羰基（B）上。在大鼠中，放射性标记的 GDC-0152 剂量的 92.2%-95.1%被回收。A 分别以尿液（62.3%）和粪便（25.1%）的形式排泄，而 B 则以尿液（27.2%）、粪便（32.2%）和呼气（27.5%）几乎相等的比例排泄。GDC-0152 经历了广泛的代谢，粪便和尿液中回收的母体药物不到剂量的 9%。同样，在血浆中，A 和 B 的总放射性曲线下面积分别为 GDC-0152 的 16.7%和 7.5%。总放射性的半衰期（t1/2）B（21.2 小时）长于 A（4.59 小时）。GDC-0152 主要通过氧化和酰胺水解进行代谢，随后进行硫酸化和葡萄糖醛酸化。循环中最丰富的代谢产物是酰胺水解产物 M26、M28、M30、M31 和 M34，占总放射性的 3.5%-9.0%。在定量全身放射自显影研究中，B 在组织中的放射性滞留时间长于 A，这与循环中总放射性的半衰期一致。一种新型的 4-苯基-5-氨基-1,2,3-噻二唑（M28）氧化裂解导致形成马尿酸（M24）。这种生物转化也在大鼠肝细胞孵育中观察到，用对取代的 M28 类似物进行孵育。此外，M24 的形成被 1-氨基苯并三唑抑制，这表明涉及到 P450 酶。
