[^(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

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 metabolic and clearance pathways of drugs in the body were deethylation,diisopropylation,oxidation,etc.Conclusion After a single oral administration of[^(14)C]birociclib suspension to healthy subjects,it was mainly cleared from the body in the form of prototype drugs and metabolites,with feces as the main excretory pathway and urine as the secondary excretory pathway.Drugs mainly undergo metabolic reactions in the body,such as deethylation,diisopropylation,and oxidation.The subjects were well tolerance after administration.