摘要
目的:研究重组人单克隆抗体 CTLA4Ig 经静脉单次给药后在 Wistar 大鼠体内的药代动力学、组织分布及排泄过程,评价剂量与药代动力学参数之间的关系。方法:54只 Wistar 大鼠(雌雄各半)分为9组(雌雄各3只),3组分别单次给药(100,30,10 mg·kg^(-1),按不同时间点采血分离血浆,TCA 沉淀法测定^(125)I-CTLA4Ig 的放射强度,用所得结果评价^(125)I-CTLA41g 在大鼠体内的暴露情况,根据非房室统计矩模型用 WinNolin 药代软件进行曲线拟合并计算药代动力学参数;其余6组单次给药30mg·kg^(-1),其中4组大鼠给药后不同时间麻醉处死、解剖测定^(125)I-CTLA4Ig 组织分布,另外1组给药后收集不同时段的尿粪评价^(125)I-CTLA4Ig 的排泄过程,最后1组麻醉后插管给药收取胆汁评价胆汁排泄。结果:Wistar 大鼠分别静脉单次注射高、中、低(100,30,10mg·kg^(-1))后,T_(1/2)分别为(41.25±0.90)h、(47.25±1.79)h 和(54.81±1.96)h,CLs 与 Vss 随着剂量的减小发生减少的变化,血药浓度-时间曲线下面积 AUC_(INF)(h·μg·mL^(-1))分别为35833.37±2618.69,14171.04±1118.25,6186.85±480.35,剂量之比为10:3:1,对应的 AUC 比值为5.8:2.3:1,剂量与 AUC 成正相关性,AUC=0.524·Dose+0.5821,相关系数 R^2=0.9975,但是 AUC 的增加量小于剂量的增加量;单次静脉给药^(125)I-CTLA4Ig 30mg·kg^(-1)后,肝肾组织中^(125)I-CTLA4Ig 的含量最高,脑含量最低;120h 经尿粪排泄量占总给药量的68.98%和6.88%;胆汁在给药后28h 其排泄量相当于总给药量的5.80%。结论:在本实验的剂量范围内,剂量与 AUC 成正相关性,AUC 的增加量小于剂量的增加量,预示在以上剂量范围内 CTLA4Ig 在 Wiatar 大鼠血浆中的浓度变化可能呈非线性药代动力学特点;肾脏为^(125)I-CTLA4Ig 的主要排泄器官;胆汁的排泄量提示^(125)I-CTLA4Ig 在大鼠体内存在肝肠循环的代谢特征。
Objective： To evaluate the pharmacokinetics, tissues distribution and excretion of CTLA4Ig in Wistar rats after single intravenous（iv） ;to assess the relationship of the pharmacokinetics parameters of CTLA4Ig vs dose. Methods： A total of 54 （27 males and 27 females） Wistar rats were divided into 9 treatments with 3 rats per gender in each group： a single iv dose of 10,30,100 mg·kg^-1 of ^125I -CTLA4Ig were given for the pharmacokinetics. A single iv dose of 30 mg·kg^-1 of ^125I -CTLA4Ig were given, four groups for the tissues distribution, one group for the excretion of urine and faeces and the final one group for the biliary excretion. ^125O - CTLA4Ig concentration in rat plasma was measured via γ count of TCA deposition. Results： The mean concentration - time curves of ^125I - CTLA4Ig was deal with noncompartment model. The main pharmacokinetic parameters as follows：T1/2 （41.25±0.90）h（47.25 ± 1.79）h and（54.81-± 1.96）h;AUCINr （35833.37 ± 2618.69） ; （14171.04 ± 1118.25）and（6186. 85 ± 480. 35）h·μg·mL^-1, respectively With the decrease of dosage, CLs and Vss were decreased. All tissues concentration of ^125I -CTLA4Ig excepting kidney and liver were lower than that in the blood,the^125I -CTLA4Ig concentration in brain was the lowest;The excretion ratios of radioactivity into urine and feces up to 120 h were 68.98% and 6. 88% after the intravenous administration and 5.80% in bile up to 28 h. Conclusion： AUC are dose - dependent pharmacokinetics but not dose -proportional over the dose range 100 -10 mg·kg^-1. Kidneys are the main route of excretion. The biliary excretion of ^125I - CTLA4Ig suggest that there are enterohepatic circulation in rats during elimination of ^125I -CTLA4Ig.
出处
《药物分析杂志》
CAS
CSCD
北大核心
2007年第7期949-953,共5页
Chinese Journal of Pharmaceutical Analysis
基金
国家"十五"重大课题专项"创新药物和中药现代化"课题"临床前安全评价关键技术及平台研究"(2002AA2Z342A)
