急进高原对普萘洛尔和美托洛尔在大鼠体内药代动力学的影响  

Effect of acute exposure to high altitude on pharmacokinetics of propranolol and metoprolol in rats

作　　者：张娟红[1] 王荣[1,2] 谢华[1] 尹强[1] 贾正平[1,2] 李文斌[1] 

机构地区：[1]兰州军区兰州总医院全军高原损伤防治重点实验室,甘肃兰州730050 [2]兰州大学药学院,甘肃兰州730050

出　　处：《南方医科大学学报》2014年第11期1616-1620,共5页Journal of Southern Medical University

基　　金：国家科技部重大资助项目(2008ZXJ09014-010);全军医药科研"十二五"重点项目(BWS12J012);全军医药科研"十二五"面上项目(CWS11C231)

摘　　要：目的研究急进高原时高原环境对普萘洛尔、美托洛尔在大鼠体内药代动力学的影响。方法将Wistar大鼠随机分为普萘洛尔平原组(P1)、普萘洛尔急进高原组(H1)、美托洛尔平原组(P2)、美托洛尔急进高原组(H2)。P1和P2组于平原地区(50 m)及H1和H2组急进高原后于高海拔地区(4010 m)禁食12 h后灌胃给药,普萘洛尔组于给药前(0 h)及给药后0.33、0.66、1、1.5、2、3、4、6、8、12、24 h由眼眶后静脉丛取血,美托洛尔组采血时间点为0、0.083、0.25、0.5、0.75、1、1.5、2、4、6、8、12、24 h。采用LCMS/MS方法测定血浆、血浆超滤液药物浓度。结果急进高原后普萘洛尔血浆蛋白结合率增高,美托洛尔组血浆蛋白结合率的变化无显著性差异。急进高原组与平原组相比,普萘洛尔在大鼠体内药代参数发生显著变化,达峰浓度(Cmax)、药-时曲线下面积(AUC)增大,平均滞留时间(MRT)、半衰期(t1/2z)延长,清除率(Clz)明显减小。美托洛尔急进高原组与平原组相比,Tmax增大,t1/2z、MRT延长,房室模型参数及其他统计矩参数的变化无显著性差异。结论急进高原后,普萘洛尔和美托洛尔在大鼠体内代谢过程发生改变。药代参数的变化除了与血浆蛋白结合率和血气指标的变化有关外,可能与药物相关代谢酶活性的改变、机体血液粘度的增高、动物种类、动物的状态不同等有关。Objective To study the pharmacokinetics of propranolol and metoprolol in rats after acute exposure to high altitude. Methods Wistar rats were randomly assigned into 4 groups for treatment with intragastric administration of propranolol or metoprolol after acute exposure to high altitude （4010 m） or normal altitude （50 m）. Venous blood samples were collected from the rats at different time points after drug administration to determine the drug concentrations in the plasma and plasma ultrafiltrate using liquid chromatography-mass spectrometry （LC-MS/MS）. Results The protein binding rate of propranolol was significantly increased but that of metoprolol remained unchanged after acute exposure to high altitude. Compared with the rats exposed to normal altitude, the rats with acute exposure to high altitude showed significant alterations in the pharmacokinetic parameters of the drugs, shown by increased Cmax and AUC, prolonged t1/2 and MRT, and lowered Clz/F of propranolol, and by increased Tmax and prolonged t1/2 and MRT of metoprolol without obvious changes of the parameters of the compartmental model. Conclusion Significant changes in the pharmacokinetics of propranolol and metoprolol occur in rats after acute exposure to high altitude possibly in relation to, apart from the changes in plasma protein binding ratio and blood gas, alterations in metabolic enzyme activities, increased blood viscosity, and species and general conditions of the animals.

关 键 词：普萘洛尔 美托洛尔 急进高原 药代动力学 蛋白结合率 

分 类 号：R96[医药卫生—药理学]