摘要
目的 减少抗病毒药阿昔洛韦 (Acyclovir ,ACV)在治疗乙型肝炎中的肝外毒副作用 ,获得肝靶向ACV偶联物。方法 多聚赖氨酸 (Poly L lysine ,PLL)在氰硼酸钠的催化作用下与乳糖反应生成乳糖化多聚赖氨酸 ,乳糖化多聚赖氨酸与咪唑化阿昔洛韦在 3 7℃pH 9 5的条件下反应合成偶联物乳糖化多聚赖氨酸 阿昔洛韦 (Lactosaminatedpoly L lysine acyclovir ,Lac PLL ACV)。偶联物经尾静脉注射进入小鼠体内后 ,收集小鼠血浆及肝脏样品 ,用高效液相色谱法测定药物浓度 ,研究偶联物的体内分布和药代动力学。结果 HPLC检测证实Lac PLL ACV在血浆中十分稳定 ,不易解离出ACV。偶联物的肝最大摄取率约为 60 % ,是ACV组的 10倍以上 ,偶联物肝中的T1/ 2 ,AUC ,CL分别为ACV的 4 2倍 ,5 6 6倍和 1/ 5 7,具有明显的肝靶向性。结论 乳糖化多聚赖氨酸作为肝去唾液酸糖蛋白受体 (Asialoglycoproteinreceptor ,ASGPR)介导的一种药物载体 。
Objective To reduce extrahepatic side effects of ACV in treatment of chronic hepatitis B , the drug was conjugated with lactosaminated poly L lysine (Lac PLL) which selectively enters hepatocyte by Asialoglycoprotein receptor. Methods Lactosylation of the poly L lysine was performed by reductive lactosamination in the presence of sodium cyanoborohydride. The conjugate Lac PLL ACV was prepared via the ACV imidazolides incubated with lactosaminated poly L lysine at 37 ℃ under pH9.5. Pharmacokinetic properties of the conjugate were studied by determining ACV concentration in plasma and liver by HPLC after intravenously administered to Kunming mice. Results The conjugate was stable in human plasma. After i.v. injection, maximally about 60% of the injected dose was taken up by the liver. The T 1/2 ,AUC, CL values in liver were about 4.2,56.6,1/57 times of the i.v.ACV group.Conclusion The results suggested that the Lac PLL were a suitable carrier for targeting antiviral drugs ACV to liver.
出处
《第三军医大学学报》
CAS
CSCD
北大核心
2002年第3期311-313,共3页
Journal of Third Military Medical University
