Takahashi Ryan H, Halladay Jason S, Siu Michael, Chen Yuan, Hop Cornelis E C A, Khojasteh S Cyrus, Ma Shuguang
Departments of Drug Metabolism and Pharmacokinetics (R.H.T., J.S.H., Y.C., C.E.C.A.H., S.C.K., S.M.), and Discovery Chemistry (M.S.), Genentech, Inc., 1 DNA Way, South San Francisco, California
Departments of Drug Metabolism and Pharmacokinetics (R.H.T., J.S.H., Y.C., C.E.C.A.H., S.C.K., S.M.), and Discovery Chemistry (M.S.), Genentech, Inc., 1 DNA Way, South San Francisco, California.
Drug Metab Dispos. 2017 May;45(5):430-440. doi: 10.1124/dmd.116.074336. Epub 2017 Feb 10.
GDC-0425 [5-((1-ethylpiperidin-4-yl)oxy)-9H-pyrrolo[2,3-b:5,4-c']dipyridine-6-carbonitrile] is an orally bioavailable small-molecule inhibitor of checkpoint kinase 1 that was investigated as a novel cotherapy to potentiate chemotherapeutic drugs, such as gemcitabine. In a radiolabeled absorption, distribution, metabolism, and excretion study in Sprague-Dawley rats, trace-level but long-lived C-labeled thiocyanate was observed in circulation. This thiocyanate originated from metabolic decyanation of GDC-0425 and rapid conversion of cyanide to thiocyanate. Excretion studies indicated decyanation was a minor metabolic pathway, but placing C at nitrile magnified its observation. Cytochrome P450s catalyzed the oxidative decyanation reaction in vitro when tested with liver microsomes, and in the presence of O, one atom of O was incorporated into the decyanated product. To translate this finding to a clinical risk assessment, the total circulating levels of thiocyanate (endogenous plus drug-derived) were measured following repeated administration of GDC-0425 to rats and cynomolgus monkeys. No overt increases were observed with thiocyanate concentrations of 121-154 M in rats and 71-110 M in monkeys receiving vehicle and all tested doses of GDC-0425. These findings were consistent with results from the radiolabel rat study where decyanation accounted for conversion of <1% of the administered GDC-0425 and contributed less than 1 M thiocyanate to systemic levels. Further, in vitro studies showed only trace oxidative decyanation for humans. These data indicated that, although cyanide was metabolically released from GDC-0425 and formed low levels of thiocyanate, this pathway was a minor route of metabolism, and GDC-0425-related increases in systemic thiocyanate were unlikely to pose safety concerns for subjects of clinical studies.
GDC-0425[5-((1-乙基哌啶-4-基)氧基)-9H-吡咯并[2,3-b:5,4-c']二吡啶-6-腈]是一种口服生物可利用的小分子检查点激酶1抑制剂，曾作为一种新型辅助疗法用于增强吉西他滨等化疗药物的疗效。在一项针对Sprague-Dawley大鼠的放射性标记吸收、分布、代谢和排泄研究中，在循环系统中观察到痕量但持久的碳标记硫氰酸盐。这种硫氰酸盐源自GDC-0425的代谢脱氰作用以及氰化物向硫氰酸盐的快速转化。排泄研究表明脱氰是一条次要的代谢途径，但将碳置于腈基上会增加其可观测性。当用肝微粒体进行测试时，细胞色素P450在体外催化氧化脱氰反应，并且在有氧存在的情况下，一个氧原子会掺入脱氰产物中。为了将这一发现转化为临床风险评估，在对大鼠和食蟹猴重复给药GDC-0425后，测量了硫氰酸盐的总循环水平（内源性加上药物衍生的）。在接受赋形剂和所有测试剂量GDC-0425的大鼠中，硫氰酸盐浓度为121 - 154 μM，在猴子中为71 - 110 μM，均未观察到明显升高。这些发现与放射性标记大鼠研究的结果一致，在该研究中，脱氰作用导致给药的GDC-0425转化不足1%，并且对全身水平的硫氰酸盐贡献小于1 μM。此外，体外研究表明人类仅存在痕量的氧化脱氰作用。这些数据表明，尽管氰化物从GDC-0425中代谢释放并形成低水平的硫氰酸盐，但该途径是一条次要的代谢途径，并且GDC-0425相关的全身硫氰酸盐增加不太可能对临床研究受试者构成安全问题。
