Bayer AG, Wuppertal, Germany.
Bayer AG, Berlin, Germany.
Cancer Chemother Pharmacol. 2018 Jan;81(1):195-206. doi: 10.1007/s00280-017-3480-9. Epub 2017 Nov 29.
To evaluate the mass balance, metabolic disposition, and pharmacokinetics of a single dose of regorafenib in healthy volunteers. In addition, in vitro metabolism of regorafenib in human hepatocytes was investigated.
Four healthy male subjects received one 120 mg oral dose of regorafenib containing approximately 100 µCi (3.7 MBq) [C]regorafenib. Plasma concentrations of parent drug were derived from HPLC-MS/MS analysis and total radioactivity from liquid scintillation counting (LSC). Radiocarbon analyses used HPLC with fraction collection followed by LSC for all urine samples, plasma, and fecal homogenate extracts. For the in vitro study, [C]regorafenib was incubated with human hepatocytes and analyzed using HPLC-LSC and HPLC-HRMS/MS.
Regorafenib was the major component in plasma, while metabolite M-2 (pyridine N-oxide) was the most prominent metabolite. Metabolites M-5 (demethylated pyridine N-oxide) and M-7 (N-glucuronide) were identified as minor plasma components. The mean concentration of total radioactivity in plasma/whole blood appeared to plateau at 1-4 h and again at 6-24 h post-dose. In total, 90.5% of administered radioactivity was recovered in the excreta within a collection interval of 12 days, most of which (71.2%) was eliminated in feces, while excretion via urine accounted for 19.3%. Regorafenib (47.2%) was the most prominent component in feces and was not excreted into urine. Excreted metabolites resulted from oxidative metabolism and glucuronidation.
Regorafenib was eliminated predominantly in feces as well as by hepatic biotransformation. The multiple biotransformation pathways of regorafenib decrease the risk of pharmacokinetic drug-drug interactions.
评估健康志愿者单次给予regorafenib 后的物质平衡、代谢分布和药代动力学。此外，还研究了人肝细胞中regorafenib 的体外代谢情况。
4 名健康男性志愿者单次口服 120mg 含有约 100µCi（3.7MBq）[C]regorafenib 的受试药物。采用 HPLC-MS/MS 分析法测定原型药物的血药浓度，采用液体闪烁计数法（LSC）测定总放射性。对所有尿液、血浆和粪便匀浆提取液均采用 HPLC 结合馏分收集后 LSC 进行放射性碳分析。体外研究中，采用 HPLC-LSC 和 HPLC-HRMS/MS 分析法对 [C]regorafenib 进行孵育分析。
regorafenib 是血浆中的主要成分，而代谢物 M-2（吡啶 N-氧化物）是最主要的代谢产物。鉴定出代谢物 M-5（去甲基吡啶 N-氧化物）和 M-7（N-葡萄糖醛酸苷）为次要的血浆成分。给药后 1-4h 和 6-24h 时，血浆/全血中总放射性浓度似乎达到平台期。在 12 天的收集间隔内，12 天内共回收 90.5%的放射性排泄物，其中大部分（71.2%）通过粪便排泄，而尿液排泄仅占 19.3%。regorafenib（47.2%）是粪便中最主要的成分，并未通过尿液排泄。排泄的代谢物来自氧化代谢和葡萄糖醛酸化。
regorafenib 主要通过粪便排泄和肝生物转化消除。regorafenib 的多种生物转化途径降低了药代动力学药物相互作用的风险。
