Ge Xinyu, Ma Sheng, Yan Shu, Wu Yali, Chen Chong, Tang Chongzhuang, Zhan Yan, Bian Yi-Cong, Shen Kai, Feng Sheng, Gao Xuehu, Zhong Dafang, Zhang Hua, Miao Li-Yan, Diao Xing-Xing
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Xenobiotica. 2023 Feb;53(2):69-83. doi: 10.1080/00498254.2023.2176267. Epub 2023 Feb 12.
SHR0302, a selective JAK1 inhibitor developed by Jiangsu Hengrui Pharmaceutical Co., was intended for the treatment of rheumatoid arthritis. In this study, we evaluated the pharmacokinetics, mass balance, and metabolism of SHR0302 in six healthy Chinese male subjects after a single 8 mg (80 µCi) oral dose of [C]SHR0302.SHR0302 was absorbed rapidly ( = 0.505 h), and the average of the SHR0302-related components in plasma was approximately 9.18 h. After an oral dose was administered, the average cumulative excretion of the radioactive components was 100.56% ± 1.51%, including 60.95% ± 11.62% in urine and 39.61% ± 10.52% in faeces.A total of 16 metabolites were identified. In plasma, the parent drug SHR0302 accounted for 90.42% of the total plasma radioactivity. In urine, SHR161279 was the main metabolite, accounting for 33.61% of the dose, whereas the parent drug SHR0302 only accounted for 5.1% of the dose. In faeces, the parent drug SHR0302 accounted for 23.73% of the dose, and SHR161279 was the significant metabolite, accounting for 5.67% of the dose. In conclusion, SHR0302-related radioactivity was mainly excreted through urine (60.95%) and secondarily through faeces (39.61%).The metabolic reaction of SHR0302 in the human body is mainly through mono-oxidation and glucuronidation. The main metabolic location of SHR0302 in the human body is the pyrrolopyrimidine ring.
SHR0302是江苏恒瑞医药股份有限公司研发的一种选择性JAK1抑制剂，用于治疗类风湿性关节炎。在本研究中，我们评估了6名健康中国男性受试者单次口服8毫克（80微居里）[C]SHR0302后SHR0302的药代动力学、质量平衡和代谢情况。SHR0302吸收迅速（t₁/₂ = 0.505小时），血浆中与SHR0302相关成分的平均t₁/₂约为9.18小时。口服给药后，放射性成分的平均累积排泄率为100.56%±1.51%，其中尿液中为60.95%±11.62%，粪便中为39.61%±10.52%。共鉴定出16种代谢物。在血浆中，母体药物SHR0302占血浆总放射性的90.42%。在尿液中，SHR161279是主要代谢物，占给药剂量的33.61%，而母体药物SHR0302仅占给药剂量的5.1%。在粪便中，母体药物SHR0302占给药剂量的23.73%，SHR161279是主要代谢物，占给药剂量的5.67%。总之，与SHR0302相关的放射性主要通过尿液（60.95%）排泄，其次通过粪便（39.61%）排泄。SHR0302在人体内的代谢反应主要通过单氧化和葡萄糖醛酸化。SHR0302在人体内的主要代谢部位是吡咯并嘧啶环。
