Kupffer细胞对奥美拉唑在小鼠体内药代动力学的影响  

Influence of Kupffer’s Cells on Pharmacokinetics of Omeprozole in Mice

作　　者：丁虹[1] 袁娴芬[1] 殷善叶[1] 童静[1] 吴世成[1] 尹登科[1] 

机构地区：[1]武汉大学药学院,武汉430072

出　　处：《中国药师》2004年第11期831-833,共3页China Pharmacist

基　　金：973国家自然科学基金资助项目 (No .2 0 0 2ccc0 0 3 0 0 )

摘　　要：目的 :观察在采用Kupffer细胞选择性阻断剂 -GdCl3 封闭小鼠肝Kupffer细胞活性后 ,奥美拉唑在小鼠体内的代谢动力学变化 ,以进一步探讨Kupffer细胞对药物代谢的影响。 方法 :雄性昆明种小鼠一次性给予GdCl3 (ip ,2 0mg·kg-1) ,于阻断后 6d ,碳粒廓清法测定小鼠的吞噬功能 ;免疫组化法观察CD68在肝脏中的表达 ;取血清测定ALT活性 ,尿素氮及肌酐含量 ,观察Kupffer细胞阻断对肝、肾功能的影响。另取同样处理的小鼠 ,给予奥美拉唑 (iv ,10mg·kg-1) ,分别于给药后 5 ,15 ,30min和 1,2 ,4 ,6 ,8,12 ,2 4h眼眶采血 ,高效液相色谱法测定血药浓度 ,3P87软件计算药代动力学参数。结果 :ipGdCl3 后 ,能明显阻断Kupffer细胞活性 ,肝、肾功能未见受损。奥美拉唑在小鼠体内药动学符合一房室模型。与正常鼠相比 ,奥美拉唑在Kupffer细胞活性阻断的小鼠体内的消除受到明显抑制。K ,CL分别下降 18.7% ,2 .9% ,t1/2 延长 18%。结论 :阻断Kupf fer细胞活性可明显改变奥美拉唑在小鼠体内的代谢与处置 ,提示Kupffer细胞在药物代谢中的作用 。Objective: To study the effect of Kupffer’s cells mediated drug metabolism.Method: To decrease the number and the function of kupffer’s cells selectively, Kunming male mice were ip injected with a single dose of gadolinium chloride (GdCl 3, 20 mg·kg -1 ). After 6 d, the normal mice and those treated with Gdcl 3 were iv injected through the tail with omeprozole at 10 mg·kg -1 , then blood samples were collected from the eye socket vein of the mice after injection at 5,15, and 30 min as well as 1, 2, 4, 6, 8, 12, and 24 h. The omeprozole concentration in blood was determined by HPLC. The pharmacokinetic parameters were calculated with 3p87 pharmacokinetics software. Moreover, the same mice treated with GdCl 3 were used to observe the serum alanine aminotransferase level(ALT) as indexes of hepatotoxicity, serum creatinine (Cr); urea nitrogen (BUN) content as indexes of renal toxicity, and the phagocytic activity (k) with Indian ink injection, and the expression of CD 68 (the specific surface antigen of macrophage)in liver tissue with immunohistochemical analysis as index of the Kupffer’s cells’ function. Result: The activity of Kupffer’s cells was obviously blocked and no hepato and nephro toxicity were observed after the administration of GdCl 3. The curve for omeprazole fitted with one compartment model in mice. Omeprazole elimination was inhibited in the mice treated with GdCl 3 compared with those of normal mice. K was decreased by 18.7% ( P < 0.05 ), t 1/2 was prolonged by 18% ( P < 0.05 ), CL was reduced by 2.9% ( P < 0.001 ).Conclusion: Kupffer’s cells blockage can markedly change the drug metabolism tendency of omeprozole.

关 键 词：KUPFFER细胞 奥美拉唑 药代动力学 

分 类 号：R969.1[医药卫生—药理学]