曲美替尼
MEK抑制剂
药理学
代谢物
排泄
药代动力学
化学
葡萄糖醛酸
内科学
MAPK/ERK通路
医学
激酶
生物化学
作者
May Y. K. Ho,Michael J. Morris,Jill Pirhalla,J.D. Bauman,Carolyn Pendry,Keith Orford,Royce Morrison,Donna S. Cox
出处
期刊:Xenobiotica
[Informa]
日期:2013-08-23
卷期号:44 (4): 352-368
被引量:20
标识
DOI:10.3109/00498254.2013.831143
摘要
1. This study assessed the mass balance, metabolism and disposition of [14C]trametinib, a first-in-class mitogen-activated extracellular signal-related kinase (MEK) inhibitor, as an open-label, single solution dose (2 mg, 2.9 MBq [79 µCi]) in two male subjects with advanced cancer.2. Trametinib absorption was rapid. Excretion was primarily via feces (∼81% of excreted dose); minor route was urinary (∼19% of excreted dose). The primary metabolic elimination route was deacetylation alone or in combination with hydroxylation. Circulating drug-related component profiles (composed of parent with metabolites) were similar to those found in elimination together with N-glucuronide of deacetylation product. Metabolite analysis was only possible from <50% of administered dose; therefore, percent of excreted dose (defined as fraction of percent of administered dose recovery over total dose recovered in excreta) was used to assess the relative importance of excretion and metabolite routes. The long elimination half-life (∼10 days) favoring sustained targeted activity was important in permitting trametinib to be the first MEK inhibitor with clinical activity in late stage clinical studies.3. This study exemplifies the challenges and adaptability needed to understand the metabolism and disposition of an anticancer agent, like trametinib, with both low exposure and a long elimination half-life.
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