Dubbelman Anne-Charlotte, Nijenhuis Cynthia M, Jansen Robert S, Rosing Hilde, Mizuo Hitoshi, Kawaguchi Shinki, Critchley David, Shumaker Robert, Schellens Jan H M, Beijnen Jos H
The Netherlands Cancer Institute, Division of Clinical Pharmacology, Department of Medical Oncology, Amsterdam, The Netherlands.
Antoni van Leeuwenhoek / The Netherlands Cancer Institute and MC Slotervaart, Department of Pharmacy & Pharmacology, Louwesweg 6, 1066 CE, Amsterdam, The Netherlands.
Invest New Drugs. 2016 Jun;34(3):300-18. doi: 10.1007/s10637-016-0342-y. Epub 2016 Mar 28.
Lenvatinib is an oral, multiple receptor tyrosine kinase inhibitor. Preclinical drug metabolism studies showed unique metabolic pathways for lenvatinib in monkeys and rats. A human mass balance study demonstrated that lenvatinib related material is mainly excreted via feces with a small fraction as unchanged parent drug, but little is reported about its metabolic fate. The objective of the current study was to further elucidate the metabolic pathways of lenvatinib in humans and to compare these results to the metabolism in rats and monkeys. To this end, we used plasma, urine and feces collected in a human mass balance study after a single 24 mg (100 μCi) oral dose of (14)C-lenvatinib. Metabolites of (14)C-lenvatinib were identified using liquid chromatography (high resolution) mass spectrometry with off-line radioactivity detection. Close to 50 lenvatinib-related compounds were detected. In humans, unchanged lenvatinib accounted for 97 % of the radioactivity in plasma, and comprised 0.38 and 2.5 % of the administered dose excreted in urine and feces, respectively. The primary biotransformation pathways of lenvatinib were hydrolysis, oxidation and hydroxylation, N-oxidation, dealkylation and glucuronidation. Various combinations of these conversions with modifications, including hydrolysis, gluthathione/cysteine conjugation, intramolecular rearrangement and dimerization, were observed. Some metabolites seem to be unique to the investigated species (human, rat, monkey). Because all lenvatinib metabolites in human plasma were at very low levels compared to lenvatinib, only lenvatinib is expected to contribute to the pharmacological effects in humans.
乐伐替尼是一种口服的多受体酪氨酸激酶抑制剂。临床前药物代谢研究显示，乐伐替尼在猴子和大鼠体内有独特的代谢途径。一项人体质量平衡研究表明，与乐伐替尼相关的物质主要通过粪便排泄，只有一小部分以未改变的母体药物形式排出，但其代谢命运鲜见报道。本研究的目的是进一步阐明乐伐替尼在人体内的代谢途径，并将这些结果与大鼠和猴子的代谢情况进行比较。为此，我们使用了在单次口服24毫克（100微居里）(14)C-乐伐替尼后的人体质量平衡研究中收集的血浆、尿液和粪便。使用液相色谱（高分辨率）质谱联用离线放射性检测法鉴定(14)C-乐伐替尼的代谢产物。检测到近50种与乐伐替尼相关的化合物。在人体内，未改变的乐伐替尼占血浆中放射性的97%，分别占尿液和粪便中排泄的给药剂量的0.38%和2.5%。乐伐替尼的主要生物转化途径是水解、氧化和羟基化、N-氧化、脱烷基化和葡萄糖醛酸化。观察到这些转化与修饰的各种组合，包括水解、谷胱甘肽/半胱氨酸结合、分子内重排和二聚化。一些代谢产物似乎是所研究物种（人类、大鼠、猴子）特有的。由于与乐伐替尼相比，人血浆中所有乐伐替尼代谢产物的水平都非常低，因此预计只有乐伐替尼会对人体的药理作用有贡献。
