Pharmacokinetics, Mass Balance, and Metabolism of [14C]SAF-189s, a Potent ALK/ROS1 Inhibitor in Humans: Metabolism Potentially Affected by Interaction of Cytochrome P450 Enzymes and Intestinal Microbiota
SAF-189s is a promising highly selective, brain-penetrant, next-generation inhibitor of anaplasticlymphoma kinase (ALK)and oncogenic c-ros oncogene (ROS1). The pharmacokinetics, massbalance, and metabolism of SAF-189s were measured in six healthy Chinese male subjects afterreceiving a single oral dose of 160 mg [14C]SAF-189s (150 Ci). SAF-189s was rapidly absorbedwith a median Tmax of 4.0 h. The arithmetic mean half-life of total radioactivity in plasma wasapproximately 32.1 h. The ratio of mean total drug-related substance concentration in whole bloodto that in plasma (B/PAUC) was 3.06, indicating that the drug was predominantly distributed inblood cells. After 336 h of drug administration, the average cumulative excretion of radioactivityaccounted for 96.98% of the total dose, with 6.24% of the drug excreted in urine and 90.74% ofthe drug excreted in feces. In total, 14 metabolites were identified. SAF-189s was the predominantcomponent in plasma but was scarcely detected in urine and feces. Oxidative metabolism mediatedby CYP3A4 was determined to be the primary metabolic pathway for SAF-189s, with theisopropyl group being the most susceptible metabolizing site. M543 was identified as the mainoxidative metabolite of SAF-189s in humans, and its production was likely affected by bothCYP3A and intestinal microbiota. Following a single oral dose of [14C]SAF-189s, SAF-189s andits principal metabolites were primarily excreted via feces. The main metabolic pathway wasoxidation, likely catalyzed by both CYP3A and intestinal microbiota.
Yuan, Yali、Zeng, Zijian、Hu, Tao、Zhong, Dafang、Miao, Liyan、iao, Xingxing、Yang, Ming、iao, Lei、Yan, Shu、an, Yan、Liu, Donghui
Shanghai Center for Drug Metabolism and Pharmacokinetics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P. R. China Shanghai Center for Drug Metabolism and Pharmacokinetics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P. R. China Institute for Interdisciplinary Drug Research and Translational Sciences, Soochow University, Suzhou, P.R.China;Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University, Suzhou, P. R. ChinaShanghai Center for Drug Metabolism and Pharmacokinetics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P. R. China Institute for Interdisciplinary Drug Research and Translational Sciences, Soochow University, Suzhou, P.R.China;Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University, Suzhou, P. R. ChinaSchool of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, P. R. China;Shanghai Center for Drug Metabolism and Pharmacokinetics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P. R. China School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, P. R. China;Shanghai Center for Drug Metabolism and Pharmacokinetics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P. R. China Fosun PharmaShanghai Center for Drug Metabolism and Pharmacokinetics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P. R. China Fosun PharmaSchool of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, P. R. China;Shanghai Center for Drug Metabolism and Pharmacokinetics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P. R. China
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14C]SAF-189sSAF-189s metabolism and pharmacokineticsNSCLCLK/ROS1 inhibitorintestinal floraYP450 enzymesclinical DDI
14C]SAF-189sSAF-189s metabolism and pharmacokineticsNSCLCLK/ROS1 inhibitorintestinal floraYP450 enzymesclinical DDI
Yuan, Yali,Zeng, Zijian,Hu, Tao,Zhong, Dafang,Miao, Liyan,iao, Xingxing,Yang, Ming,iao, Lei,Yan, Shu,an, Yan,Liu, Donghui.Pharmacokinetics, Mass Balance, and Metabolism of [14C]SAF-189s, a Potent ALK/ROS1 Inhibitor in Humans: Metabolism Potentially Affected by Interaction of Cytochrome P450 Enzymes and Intestinal Microbiota[EB/OL].(2025-07-28)[2025-08-02].https://chinaxiv.org/abs/202507.00455.点此复制
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