反义核酸药物KS0604在小鼠的组织分布  

Tissue distribution of phosphorothioate antisense oligonucleotide KS0604 in mice

作　　者：王诗鸿[1] 王秀中[1] 王彤[2] 向慎思[2] 王清清[2] 宋海峰[2] 刘秀文[2] 

机构地区：[1]解放军第188医院,潮州521000 [2]军事医学科学院放射与辐射医学研究所,北京100850

出　　处：《中国新药杂志》2012年第12期1341-1345,共5页Chinese Journal of New Drugs

摘　　要：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 establish a method for quantitation of KS0604（30 mg·kg-1） in mouse tissues and plasma,and evaluate the tissues distribution of KS0604 in mice.Methods： A dual solid phase extraction（SPE） pretreatment coupling with non-gel sieving capillary electrophoresis（NGCE） was performed for the quantitative determination of KS0604 in plasma and tissues of mice after iv administered single doses of 30 mg·kg-1.Results： The calibration curve for KS0604 was linear over corresponding concentration ranges in blank tissues or plasma with correlation coefficients（r） of more than 0.99.Following iv administration,its plasma concentration showed a rapid decline.Its highest concentrations in tissues was detected in the kidney,reaching the maxima at 2 h.Liver,lung,heart,skeletal muscle,and fat reached the maxima at 1 h.Concentrations of KS0604 in spleen for most subjects and in brain and pancreas for all subjects were lower than quantification limitation.The non-gel sieving capillary electrophoresis profiles of KS0604 in tissues showed that its full-length series was the main component in tissues,followed by its progressively degradative products.Conclusion： The combined method of solid-phase extraction and NGCE can be used to study the tissue distribution of KS0604 in mice.The original shape is the main component of KS0604 in tissues.The highest level of AUC0-t can be detected in the kidney,followed by those in liver,lung,heart,skeletal muscle,fat and plasma.

关 键 词：反义核酸 组织分布 非胶筛分毛细管电泳 小鼠 

分 类 号：R969.1[医药卫生—药理学]