Metabolism of Flumatinib, a Novel Antineoplastic Tyrosine Kinase Inhibitor, in Chronic Myelogenous Leukemia Patients

酪氨酸激酶抑制剂 CD135型 癌症研究 酪氨酸激酶 慢性粒细胞白血病 化学 白血病 药理学 医学 激酶 内科学 生物化学 癌症 受体
作者
Aishen Gong,Xiaoyan Chen,Pan Deng,Dafang Zhong
出处
期刊:Drug Metabolism and Disposition [American Society for Pharmacology & Experimental Therapeutics]
卷期号:38 (8): 1328-1340 被引量:17
标识
DOI:10.1124/dmd.110.032326
摘要

4-(4-Methyl-piperazin-1-ylmethyl)-N-[6-methyl-5-(4-pyridin-3-yl-pyrimidin-2-ylamino)-pyridin-3-yl]-3-trifluoromethyl-benzamide (flumatinib, HH-GV678), an antineoplastic tyrosine kinase inhibitor, is currently in Phase I clinical trials in China for the treatment of chronic myelogenous leukemia (CML). The purpose of this study was to identify the metabolites of flumatinib in CML patients, with the aim of determining the main metabolic pathways of flumatinib in humans after oral administration. Ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry revealed 34 metabolites; 7 primary metabolites were confirmed by comparison with synthetic reference standards. The results show that the parent drug flumatinib was the main form recovered in human plasma, urine, and feces. The main metabolites of flumatinib in humans were the products of N-demethylation, N-oxidation, hydroxylation, and amide hydrolysis. In addition to these phase I metabolites, several phase II glucuronidation and acetylation products were detected in plasma, urine, and feces. The observed circulating metabolites included an N-demethylated metabolite (M1), two hydrolytic metabolites (M3, M4), oxidation metabolites (M2-1, M2-4, M2-7, M2-9, and M14), a glucuronide conjugate (M16-2), and several multiple metabolic products. Flumatinib was predominantly metabolized by amide bond cleavage to yield two corresponding hydrolytic products. By comparison with the related drug 4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (imatinib), we concluded that the electron-withdrawing groups of trifluoromethyl and pyridine facilitated the amide bond cleavage and led to the in vivo formation of a carboxylic acid and an amine.
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