新型c-Myc反义硫代磷酸寡脱氧核苷酸在小鼠体内的药动学

目的 :研究新筛选合成的c Myc基因反义硫代磷酸寡脱氧核苷酸 (antisensephosphorothioateoligodeoxynucleotidestoc Myc ,c MycAS PS ODN )在小鼠体内的药动学、组织分布和排泄情况。方法 :给小鼠按 5 ,10 ,2 0mg·kg- 13个剂量静脉注射3H c MycAS PS ODN后 ,液闪仪测定不同时间点血浆药物浓度 ;按 10mg·kg- 1静脉注射3H c MycAS PS ODN ,测定不同时间组织器官中3H c MycAS PS ODN的含量和其在粪、尿中排泄率 ,药动学统计程序拟合分析。结果 :静脉注射后 3种剂量血浆药物浓度 时间曲线均符合二室分布模型 ,3种剂量下的AUC之间有明显的线性关系 ;多数组织药物分布浓度 2h达高峰 ,肝、脾、肾、肺和骨髓中药物浓度较高 ,2 4h尿、粪总排泄率 82 %。结论 :c MycAS PS ODN在体内分布快 ,除脑、生殖腺等亲脂性组织外 ,其他组织含量高 ;主要通过尿液排泄。

Pharmacokinetics of a novel c-Myc antisense phosphorothioate oligodeoxynucleotide in mice

AIM: To investigate the pharmacokinetics, distribution of tissue, and excretion of 3H-radiolabeled c-Myc antisense phosphorothioate oligodeoxynucleotide ( 3H-c-Myc AS-PS-ODN) after single intravenous administration in mice. METHODS: The plasma radioactivities of 3H-c-Myc AS-PS-ODN administered intravenously in mice at three dose of 5, 10, 20 mg·kg -1 respectively were assayed at several time points by liquid sciuntillation counting; in addition, the radioactivity in tissues and the radioactivity of excretion in urine, feces were detected at several time points after administration of 3H-Myc-AS-PS-ODN intravenously at the dose of 10 mg·kg -1, then the profile was analysed by pharmacokinetics system. RESULTS: A two-compartment model was selected as optional model. There was a linear relationship between the doses administered and the AUC. c-Myc AS-PS-ODN distributed extensively into tissues, but the relative affinity varied enormously, being higher for kidney, liver, spleen, and bone marrow and lower for other tissues. There was little c-Myc AS-PS-ODN distributing into brain, reproductive gland and fat. Within the first 24 h, the urinary excretion was reached 82 % of the administered dose, which was extraordinarily more than the excretion in feces. CONCLUSION: Distribution and elimination of c-Myc AS-PS-ODN is rapid except brain, reproduction gland and fat. C-Myc AS-PS-ODN is mainly excreted in urine.