健康男性体内表皮生长因子受体外显子 20 插入突变体选择性共价抑制剂 [14C]mobocertinib 的代谢和排泄。

IF 4.4 3区 医学 Q1 PHARMACOLOGY & PHARMACY
Hao Chen, Abhi Shah, Suguru Kato, Robert Griffin, Steven Zhang, Sandeepraj Pusalkar, Lawrence Cohen, Yuexian Li, Swapan K Chowdhury, Sean Xiaochun Zhu
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引用次数: 0

摘要

莫博克替尼(原名 TAK-788)是一种针对 20 号外显子插入突变的表皮生长因子受体的共价酪氨酸激酶抑制剂。本文描述了健康男性受试者单次口服[14C]莫博克替尼后莫博克替尼的代谢和排泄情况。莫博克替尼相关物质与血浆蛋白(如人血清白蛋白)高度共价结合。在 6 份汉密尔顿血浆样本中,总放射性的平均提取回收率仅为 3.9%。提取后,莫博凯替尼是含量最高的成分,占上清液中提取的循环放射性总量(TECRA)的7.7%。已确定的代谢物中,每种代谢物都占到了7.7%。 重要声明 本手稿描述了靶向共价抑制剂莫博克替尼在人体单次口服[14C]莫博克替尼后的代谢和排泄情况。莫博克替尼与人体血浆蛋白高度共价结合。在人体血浆中,提取的循环放射性总量中没有一种代谢物超过10%。莫博替尼主要通过CYP3A4/5介导的氧化代谢排出体外,约91.7%的剂量被吸收后随粪便排出体外。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Metabolism and Excretion of [14C]Mobocertinib, a Selective Covalent Inhibitor of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations, in Healthy Male Subjects.

Mobocertinib (formerly known as TAK-788) is a targeted covalent tyrosine kinase inhibitor of epidermal growth factor receptor with exon 20 insertion mutations. This article describes the metabolism and excretion of mobocertinib in healthy male subjects after a single oral administration of [14C]mobocertinib. Mobocertinib-related materials were highly covalently bound to plasma proteins such as human serum albumin. The mean extraction recovery of total radioactivity was only 3.9% for six individual Hamilton pooled plasma samples. After extraction, mobocertinib was the most abundant component accounting for 7.7% of total extracted circulating radioactivity (TECRA) in the supernatant. Each of identified metabolites accounted for <10% of TECRA. Mobocertinib underwent extensive first-pass metabolism with the fraction of the dose absorbed estimated to be approximately 91.7%. Fecal excretion of mobocertinib metabolites was the major elimination route. Mobocertinib was mainly eliminated via oxidative metabolism with a fraction of approximately 88% metabolized by CYP3A4/5. The other minor elimination pathways included cysteine conjugation, metabolism by other cytochrome P450s, and renal excretion of unchanged mobocertinib. SIGNIFICANCE STATEMENT: This article describes the metabolism and excretion of a targeted covalent inhibitor mobocertinib in humans after a single oral administration of [14C]mobocertinib. Mobocertinib was highly covalently bound to human plasma proteins. No metabolite accounted for >10% of total extracted circulating radioactivity in human plasma. Mobocertinib was mainly eliminated via CYP3A4/5 mediated oxidative metabolism followed by fecal excretion after approximately 91.7% of the dose was absorbed.

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来源期刊
CiteScore
6.50
自引率
12.80%
发文量
128
审稿时长
3 months
期刊介绍: An important reference for all pharmacology and toxicology departments, DMD is also a valuable resource for medicinal chemists involved in drug design and biochemists with an interest in drug metabolism, expression of drug metabolizing enzymes, and regulation of drug metabolizing enzyme gene expression. Articles provide experimental results from in vitro and in vivo systems that bring you significant and original information on metabolism and disposition of endogenous and exogenous compounds, including pharmacologic agents and environmental chemicals.
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