Pharmacokinetics, mass balance, and metabolism of [14C]SAF-189s, a potent anaplastic lymphoma kinase/c-ROS proto-oncogene 1 inhibitor in humans: Metabolism potentially affected by interaction of cytochrome P450 enzymes and intestinal microbiota
文献类型：期刊论文
| 作者 | Yang, Ming4,5; Diao, Lei3; Yan, Shu4; Tan, Yan3; Liu, Donghui4,5; Yuan, Yali4; Zeng, Zijian4; Hu, Tao1,2; Zhong, Dafang4; Miao, Liyan1,2 |
| 刊名 | DRUG METABOLISM AND DISPOSITION
 |
| 出版日期 | 2025-09-01 |
| 卷号 | 53期号:9页码:14 |
| 关键词 | [C-14]SAF-189s SAF-189s metabolism and pharmacokinetics Non-small cell lung cancer ALK/ROS1 inhibitor Intestinal flora P450 enzymes |
| ISSN号 | 0090-9556 |
| DOI | 10.1016/j.dmd.2025.100131 |
| 通讯作者 | Miao, Liyan(miaolysuzhou@163.com) ; Diao, Xingxing(xxdiao@simm.ac.cn) |
| 英文摘要 | SAF-189s is a promising highly selective, brain-penetrant, next-generation inhibitor of anaplastic lymphoma kinase (ALK) and c-ROS proto-oncogene 1 (ROS1). The pharmacokinetics, mass balance, and metabolism of SAF-189s were measured in 6 healthy Chinese male participants after receiving a single oral dose of 160 mg [C-14]SAF-189s (150 mu Ci). SAF-189s was rapidly absorbed with a median T-max of 4.0 hours. The arithmetic mean half-life of total radioactivity in plasma was approximately 32.1 hours. The ratio of mean total drug-related substance concentration in whole blood to that in plasma (B/P-AUC) was 3.06, indicating that the drug was predominantly distributed in blood cells. After 336 hours of drug administration, the average cumulative excretion of radioactivity accounted for 96.98% of the total dose, with 6.24% of the drug excreted in urine and 90.74% of the drug excreted in feces. In total, 14 metabolites were identified. SAF-189s was the predominant component in plasma but was scarcely detected in urine and feces. Oxidative metabolism mediated by CYP3A4 was determined to be the primary metabolic pathway for SAF-189s, with the isopropyl group being the most susceptible metabolizing site. M543 was identified as the main oxidative metabolite of SAF-189s in humans, and its production was likely affected by both CYP3A and intestinal microbiota. After a single oral dose of [C-14]SAF-189s, SAF-189s and its principal metabolites were primarily excreted via feces. The main metabolic pathway was oxidation, likely catalyzed by both CYP3A and intestinal microbiota. SIGNIFICANCE STATEMENT: This study investigated the absorption and disposition of SAF-189s, a promising next-generation inhibitor of ALK/ROS1 administered for the treatment of ALK+/ROS1+ non-small cell lung cancer. The results demonstrated that SAF-189s and its metabolites were primarily excreted via feces, with metabolism likely mediated by both the cytochrome P450 system and gut microbiota. These findings provide essential pharmacokinetic and safety data, encourage further studies on drug interactions and dose adjustments, and support the involvement of gut microbiota, thereby guiding future research. (c) 2025 American Society for Pharmacology and Experimental Therapeutics. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies. |
| WOS关键词 | CELL LUNG-CANCER ; 3-N-BUTYLPHTHALIDE NBP ; IDENTIFICATION ; QUANTITATION ; CRIZOTINIB ; PLASMA ; DRUGS |
| 资助项目 | Fosun Pharma ; National Natural Science Foundation of China[82373938] ; National Natural Science Foundation of China[82104275] ; National Natural Science Foundation of China[82104276] ; National Natural Science Foundation of China[82204585] ; Key Technologies R&D Program of Guangdong Province[2023B1111030004] ; National Key R&D Program of China[2022YFF1202600] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001588448200001 |
| 出版者 | ELSEVIER SCIENCE INC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/321648]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Miao, Liyan; Diao, Xingxing |
| 作者单位 | 1.Soochow Univ, Inst Interdisciplinary Drug Res & Translat Sci, Suzhou, Peoples R China 2.Soochow Univ, Affiliated Hosp 1, Dept Clin Pharmacol, 899 Pinghai Rd, Suzhou 215000, Peoples R China 3.Shanghai Fosun Pharmaceut Grp Co Ltd, Clin Res Dept, Shanghai, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai Ctr Drug Metab & Pharmacokinet, Shanghai, Peoples R China 5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China |
| 推荐引用方式 GB/T 7714 | Yang, Ming,Diao, Lei,Yan, Shu,et al. Pharmacokinetics, mass balance, and metabolism of [14C]SAF-189s, a potent anaplastic lymphoma kinase/c-ROS proto-oncogene 1 inhibitor in humans: Metabolism potentially affected by interaction of cytochrome P450 enzymes and intestinal microbiota[J]. DRUG METABOLISM AND DISPOSITION,2025,53(9):14. |
| APA | Yang, Ming.,Diao, Lei.,Yan, Shu.,Tan, Yan.,Liu, Donghui.,...&Diao, Xingxing.(2025).Pharmacokinetics, mass balance, and metabolism of [14C]SAF-189s, a potent anaplastic lymphoma kinase/c-ROS proto-oncogene 1 inhibitor in humans: Metabolism potentially affected by interaction of cytochrome P450 enzymes and intestinal microbiota.DRUG METABOLISM AND DISPOSITION,53(9),14. |
| MLA | Yang, Ming,et al."Pharmacokinetics, mass balance, and metabolism of [14C]SAF-189s, a potent anaplastic lymphoma kinase/c-ROS proto-oncogene 1 inhibitor in humans: Metabolism potentially affected by interaction of cytochrome P450 enzymes and intestinal microbiota".DRUG METABOLISM AND DISPOSITION 53.9(2025):14. |
入库方式： OAI收割
来源：上海药物研究所
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