抗肿瘤化合物MC002的活性代谢产物雷公藤内酯醇在大鼠体内药代动力学与组织分布  

Pharmacokinetics and tissue distribution of triptolide,an activemetabolite of anticancer prodrug MC002,in rats

作　　者：刘萍霞[1,2] 刘频健[3] 庄笑梅[1] 王娟[1] 张玉杰[4] 张振清[1] 阮金秀[1] 

机构地区：[1]军事医学科学院毒物药物研究所药物代谢与药代动力学重点实验室,北京100850 [2]解放军庐山疗养院药剂科,江西九江332000 [3]九江学院基础医学院,江西九江332000 [4]北京美迪克斯生物技术有限公司,北京100012

出　　处：《中国药理学与毒理学杂志》2011年第2期206-210,共5页Chinese Journal of Pharmacology and Toxicology

基　　金：国家重大新药创制"科技重大专项新药研究开发技术单元平台"(2009ZX09304-004);北京市科委重大创新药物研制资助项目(D07080201330721)~~

摘　　要：目的探讨抗肿瘤前药MC002的活性代谢产物雷公藤内酯醇(TP)在大鼠体内的药代动力学和组织分布。方法 SD大鼠iv给予MC002 0.25～2.25 mg.kg-1,于不同时间点采集血样;另SD大鼠iv给予MC002 0.75 mg.kg-1后于5,15,30和90 min后采集心、肝、脾、肺、胃等组织样品和血样。应用高效液相色谱-质谱联用方法测定全血和组织中TP的含量。DAS 2.0软件计算相关药代动力学参数。结果雄性SD大鼠iv给予MC002 0.25,0.75和2.25 mg.kg-1后,MC002在大鼠体内迅速转化为活性代谢产物TP,cmax分别为105±2,257±74和(747±154)μg.L-1;AUC分别为1827±151,5604±1141和(16 833±3654)μg.min.L-1,与MC002给药剂量呈线性正相关,消除半衰期分别为31.7±7.3,23.8±3.4和(19.2±2.5)min。大鼠iv给予MC002 0.75 mg.kg-1后5 min,大鼠各组织活性代谢产物TP含量达到最高,30 min后浓度大幅下降。结论 MC002在大鼠体内迅速转化为活性代谢产物TP。在MC002 0.25,0.75和2.25 mg.kg-1范围内,活性代谢产物TP代谢符合线性药动学特点,TP在大鼠体内广泛分布,快速消除。OBJECTIVE To investigate pharmacokinetics and tissue distribution properties oftriptolide（TP）,an active metabolite of a new anticancer prodrug MC002,in rats.METHODSSD rats were iv given MC002 0.25,0.75 and 2.25 mg.kg^-1,and blood samples were collected at0,2,5,8,12,16,20,30,45,60 and 90 min before and after administration of MC002.Tissuessamples were collected at 5,15,30 and 90 min after SD rats were iv given MC002 0.75 mg.kg^-1.Concentrations of TP in biological samples were determined by high performance liquid chromatorgra-phy-mass spectrometry（HPLC-MS/MS）.Pharmacokinetic parameters were calculated by DAS2.0software.RESULTS After male SD rats were iv given MC002 0.25,0.75 and 2.25 mg.kg^-1,MC002 was quickly metabolized to TP,an active metabolite of MC002.AUC of TP in MC002 0.25,0.75 and 2.25 mg.kg^-1 groups was 1827 ±151,5604 ±1141,and（16 833 ±3654） μg.min.L^-1,respectively,cmax was 105 ±2,257 ±74 and（747 ±154） μg.L^-1,respectively,in a linear propor-tion to MC002 dose,and t1/2 was 31.7 ±7.3,23.8 ±3.4 and（19.2 ±2.5） min,respectively.Af-ter the administration of MC002 0.75 mg.kg^-1,TP reached the peak concentration in all measuredtissues at 5 min,but decreased significantly after 30 min.CONCLUSION Prodrug MC002 isquickly transformed into TP after rats are iv given MC002.TP conforms to linear pharmacokineticswithin the range of 0.25-2.25 mg.kg^-1.TP is widely distributed but quickly eliminated in rats.

关 键 词：MC002 雷公藤内酯 药代动力学 组织分布 抗肿瘤药 

分 类 号：R969.1[医药卫生—药理学] R979.1[医药卫生—药学]