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目的:研究小鼠静脉注射30 mg.kg-1 KS0604后血浆和组织中原形药物浓度-时间变化。方法:建立组织消化结合基于离子交换和反相分配原理的两步固相萃取法,并采用非胶筛分毛细管电泳技术分析小鼠血浆和组织中的KS0604。结果:小鼠血浆和组织中KS0604在标准曲线范围内呈良好的线性关系。小鼠给药后各组织中以全长序列即药物原形为主,给药后4 h内,血浆中的浓度逐渐下降,2 h和4 h仅个别个体可测到。各组织中肾浓度一直最高,在给药后2 h达峰;肝、肺、心、骨骼肌和脂肪中,均在给药后1 h达到最高,4 h内变化不大。而脾在给药后仅个别个体可测到,脑和胰组织中的浓度均低于定量下限。结论:非胶筛分毛细管电泳方法能满足反义核酸药物KS0604小鼠组织分布实验的要求。小鼠给药后各组织中以全长序列即药物原形为主,给药后4 h内,AUC0～t从大到小依次为肾、肝、肺、心、骨骼肌、脂肪和血浆。
Objective: To study the change of concentration and time of prototype drugs in plasma and tissue after intravenous injection of 30 mg.kg-1 KS0604 in mice. METHODS: Two-step solid phase extraction (SPE) based on the principle of ion exchange and reversed phase partitioning was established for tissue digestion. KS0604 in mouse plasma and tissues was analyzed by non-gel-sieving capillary electrophoresis. Results: There was a good linear relationship between KS0604 in the plasma and tissues of mice in the standard curve. After administration of the mice, the full-length sequence, that is, the prototype of the drug, was dominant in each tissue. The concentration in the plasma gradually decreased within 4 hours after administration, and only a few individuals were detected at 2 and 4 hours. The kidney concentration in each tissue was the highest at 2 h after administration, and reached the maximum at 1 h after administration in liver, lung, heart, skeletal muscle and fat, but little changed within 4 h. The spleen in the individual only after administration of measurable, brain and pancreatic tissue concentrations were lower than the lower limit of quantitation. Conclusion: The method of non-gel sieving capillary electrophoresis can meet the requirement of tissue distribution experiment of antisense nucleic acid drug KS0604. After administration of the mice, the full-length sequence, that is, the prototype of the drug, was dominant in each tissue. Within 4 h after administration, AUC0-t was in descending order of kidney, liver, lung, heart, skeletal muscle, fat and plasma.