雷公藤甲素在Beagle犬体内毒代动力学研究  

Toxicokinetics of triptolide in Beagle dogs after oral and intravenous administration

作　　者：邵凤 孙建国[2] 王广基[2] 

机构地区：[1]南京医科大学第一附属医院I期临床研究室 [2]中国药科大学药物代谢动力学重点实验室

出　　处：《中国临床药理学与治疗学》2014年第12期1326-1331,1351,共7页Chinese Journal of Clinical Pharmacology and Therapeutics

基　　金：国家自然科学基金重点项目(30630076);科技部科技重大专项"重大新药创制"(2011ZX09302-003-02);江苏省科技重大专项(BM2011017)

摘　　要：目的:探索性研究雷公藤甲素在犬体内的毒代动力学特征,并观察其毒性反应,为雷公藤甲素毒性机制的深入研究提供研究数据。方法:25只Beagle犬随机分为5组,分别为灌胃给药A组(高剂量,0.1mg/kg)、B组(中剂量,0.08mg/kg)、C组(低剂量,0.05mg/kg),静脉给药D组(0.08mg/kg)和空白对照组E组,连续给药14d,于给药第1、7和14天采集血样或组织样本供毒代动力学研究及毒性检查(血常规、血生化、病理切片);14d给药过程中进行临床症状观察。结果:雷公藤甲素给药后第1天和第14天,静注和口服药代参数均有所变化,静注AUC0-∞从145.86增加到276.24ng·h·mL-1,CL从548.45降到301.89mL·h-1·kg-1;口服高剂量AUC0-∞从151.54增加到289.98ng·h·mL-1,Cmax从44.49增加到75.26ng/mL;口服中剂量AUC0-∞从37.78增加到61.65ng·h·mL-1,Cmax从44.49增加到75.26ng/mL;口服低剂量AUC0-∞从67.92增加到143.98ng·h·mL-1,Cmax从24.05增加到38.07ng/mL。MRT、T1/2延长。毒性观察结果显示,毒性呈剂量和时间相关性,均出现不同程度的胃肠道反应,肝功能受损,白细胞降低等。结论:本文探索性研究了雷公藤甲素在犬体内的毒代动力学的性质,提示胃肠道和肝脏可能是两个主要的毒性靶器官,同时研究发现给药途径对雷公藤甲素的安全性有较大影响。AIM： To explore the toxicokinetic properties of triptolide in Beagle dogs after oral and intravenous administration and to observe it＆#39; s toxicity for providing the further information of deeply investigating the mechanism of triptolide.METHODS： 25 Beagle dogs were divided into five groups, group A（0.1 mg/kg）, group B（0.08 mg/kg）, group C（0.05 mg/kg）by oral administration, group D（0.08 mg/kg）by intravenous administration and group E for blank control, respectively.These dogs were dosed continually for 14 days.The plasma/serum or tissue samples were collected for toxicokinetic analysis and toxic evaluation including routine biochemical assays and histopathological inspection.RESULTS： Comparing the PK parameters on Day 1, there were some changes on Day 14 after exposing to triptolide for 14 days either oral or intravenous administration.AUC0-∞ and Cmax were increased from 145.86 to 276.24 ng · h · mL^-1 and from 44.49 to 75.26 ng/mL respectively after intravenous administration of 0.08 mg/kg triptolide; For oral administration, AUC0-∞ and Cmax were increased from 151.54 to 289.98 ng· h· mL^-1 and from 44.49 to 75.26 ng/mL at the dose of 0.1 mg/kg, from 37.78 to 61.65 ng· h· mL^-1 and from 44.49 to 75.26 ng/mL at the dose of 0.08 mg/kg, from 67.92 to 143.98 ng· h· mL^-1 and from 24.05 to 38.07 ng/mL at the dose of 0.05 mg/kg.MRT and T1/2 was also longer on Day 14 than on Day 1.The observation of toxicity indicated that it was dose and time dependent, which was showed various level of gastro-intestinal reaction, liver impairments and decreased amount of white cells.CONCLUSION： It was estimated that the gastrointestinal tract and liver were the targeted toxic organs and the administration way was expected to impact the safety of triptolide in dogs.

关 键 词：毒代动力学 雷公藤甲素 毒性 

分 类 号：R965.2[医药卫生—药理学]