[^(14)C]吡罗西尼在中国男性健康受试者体内的药物代谢和排泄研究  

Drug metabolism and excretion of[^(14)C]birociclib in Chinese male healthy subjects

作　　者：庄铨坤 樊慧蓉 董世奇 范宾科 刘鸣明 许玲美 王莉 刘雪梅 侯芳 ZHUANG Quan-kun;FAN Hui-rong;DONG Shi-qi;FAN Bin-ke;LIU Ming-ming;XU Ling-mei;WANG Li;LIU Xue-mei;HOU Fang(Phase I Clinical Research Center,Beijing GoB road Boren Hospital,Beijing 100071,China;Radiopharmacokinetic Platform,Institute of Radiation Medicine,Chinese Academy of Medical Sciences,Tianjin 300110,China;Xuanzhu Biopharmaceutical Co.,Ltd.,Beijing 100020,China)

机构地区：[1]北京高博博仁医院Ⅰ期临床研究中心,北京100071 [2]中国医学科学院放射医学研究所放射性药代平台,天津300110 [3]轩竹生物科技股份有限公司,北京100020

出　　处：《中国临床药理学杂志》2024年第14期2118-2123,共6页The Chinese Journal of Clinical Pharmacology

摘　　要：目的评估中国男性健康志愿者单次口服[^(14)C]吡罗西尼后,药物在人体内的物质平衡及药代动力学特征。方法用^(14)C标记示踪的方法评价吡罗西尼的人体物质平衡和生物转化。受试者餐后单次口服[^(14)C]吡罗西尼混悬液360 mg/50μCi后,采集指定时间点/时间间隔内的血液、尿液和粪便样本。用液体闪烁计数的方法分析受试者全血、血浆、尿液和粪便中^(14)C标记吡罗西尼相关化合物的放射量。用高效液相色谱与在线/离线同位素检测仪联用获得血浆、尿液和粪便样本放射性同位素代谢物谱,结合高分辨质谱对主要代谢产物进行鉴定。结果共入组6例健康男性受试者。受试者服药后,血浆中放射性药物中位达峰时间为5.00 h,平均末端消除半衰期为43.70 h。在给药后288.00 h内,放射性药物基本从体内排泄清除,受试者平均放射性药物累积回收率为(94.10±8.19)%。放射性药物主要经粪便排泄,占给药量的(84.60±7.10)%,尿液为次要排泄途径,占给药量的9.41%。代谢分析表明,血浆中放射性药物的主要成分为原形药物,主要代谢产物为RM4(XZP-5286)、RM6(XZP-3584)、RM7(XZP-5736)。药物主要以原形药物和代谢物形式从体内清除,除原形药物外,血浆、尿液和粪便样本中共鉴定并分析了9个代谢产物,全部为Ⅰ相代谢产物。药物在体内的主要代谢清除途径为脱乙基、脱异丙基、氧化等。结论健康受试者单次口服[^(14)C]吡罗西尼混悬液后,主要以原形药物和代谢物形式从体内清除,粪便是主要排泄途径,尿液为次要排泄途径。药物在体内主要发生脱乙基、脱异丙基、氧化等代谢反应。受试者服药后,安全性和耐受性良好。Objective To evaluate the characteristics of the mass balance and pharmacokinetics of[^(14)C]birociclib in Chinese male healthy volunteers after a single oral administration.Methods This study used a^(14)C labeled method to investigate the mass balance and biological transformation of birociclib in human.Subjects were given a single oral dose of 360 mg/50μCi of[^(14)C]birociclib suspension after meals.The blood,urine,and fecal samples were collected at specified time points/intervals after administration.The radiation levels of^(14)C labeled birociclib-related compounds in the blood,plasma,urine,and feces were analyzed using liquid scintillation counting.In addition,a combination of high-performance liquid chromatography and on-line/off-line isotope detectors was used to obtain radioactive isotope metabolite spectra of plasma,urine,and fecal samples,and high-resolution mass spectrometry was used to identify the main metabolites.Results A total of 6 healthy male subjects were enrolled in this study.The median peak time of radioactive components in plasma was 5.00 h and the average terminal elimination half-life was 43.70 h after administration.The radioactive components were basically excreted and cleared from the body within 288.00 hours after administration,and average cumulative recovery rate of radioactive drugs was(94.10±8.19)%.The radioactive drugs were mainly excreted through feces,accounting for(84.60±7.10)%of the dose of radioactive drugs administered.Urine was the secondary excretory pathway,accounting for 9.41%of the dose of radioactive drugs administered.Metabolic analysis indicated that the prototype drug was the main radioactive components in plasma samples.The main metabolites in plasma were RM4(XZP-5286),RM6(XZP-3584),and RM7(XZP-5736).The drugs were mainly cleared from the body in the form of prototype drugs and metabolites.In addition to prototype drugs,a total of 9 metabolites were identified and analyzed in plasma,urine,and fecal samples,all of which were phaseⅠmetabolites.The main metabol

关 键 词：[^(14)C]吡罗西尼 物质平衡 代谢 药代动力学 同位素 

分 类 号：R979.1[医药卫生—药品]