高原低氧环境下HDAC5在大鼠体内P-gp表达中的作用及对苯妥英钠药代影响  

Study on role of HDAC5 in P-gp expression in rats in high-altitude low oxygen environment and its effect on phenytoin sodium pharmacokinetics

作　　者：赵以览 牟宏芳 张晓静 罗林 封士兰[2] 贺嘉馨 赵安鹏 王荣 ZHAO Yi-lan;MU Hong-fang;ZHANG Xiao-jing;LUO Lin;FENG Shi-lan;HE Jia-xin;ZHAO An-peng;WANG Rong(Dept of Pharmacy,the 940th Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army,Lanzhou 730050,China;Pharmacy of Lanzhou University,Lanzhou 730000,China;Gansu Plateau Pharmaceutical Technology Center,Lanzhou 730050,China)

机构地区：[1]中国人民解放军联勤保障部队第九四〇医院药剂科,甘肃兰州730050 [2]兰州大学药学院,甘肃兰州730000 [3]甘肃省高原药学行业技术中心,甘肃兰州730050

出　　处：《中国药理学通报》2023年第9期1740-1745,共6页Chinese Pharmacological Bulletin

基　　金：甘肃省青年科技基金计划(No 20JR10RA014)。

摘　　要：目的探究高原低氧环境下HDAC5在大鼠体内P-gp表达中的关键作用及对苯妥英钠药代的影响。方法Wistar大鼠运至海拔4010 m的青海玉树巴塘,每组6只。不同组分别给予苯妥英钠、苯妥英钠联用金丝桃素、苯妥英钠联用维拉帕米。在高原地区收集服药后不同时间的血浆和肝组织。采用UFLC-MS法测定血浆中苯妥英钠的浓度,计算药代动力学参数。Western blot检测肝组织中HDAC5、P-gp蛋白表达的变化。结果UFLC-MS结果表明,给予P-gp激动剂后,AUC(0-t)、AUC(0-∞)、MRT(0-t)、MRT(0-∞)、T_(1/2z)、CL_(z)/F、V_(z)/F增加;给予P-gp抑制剂后,AUC(0-t)、AUC(0-∞)、MRT(0-t)、MRT(0-∞)、T_(1/2z)降低。同时,高原低氧环境下,HDAC5参与P-gp表达的调控。当给予P-gp激动剂和抑制剂时,HDAC5与P-gp表达呈现相同变化趋势。结论高原低氧环境下,肝中转运体P-gp的表达影响了P-gp底物苯妥英钠的药代动力学,P-gp的变化水平与HDAC5有关。Aim To explore the important role of HDAC5 in P-gp expression in rats in high-altitude low oxygen environment and its effect on phenytoin sodium pharmacokinetics.Methods Wistar rats were transported to Batang,Yushu,Qinghai,at an altitude of 4010 m,with 6 rats in each group,divided into 1 d and 3 d groups.Different groups were given phenytoin,phenytoin combined with hypericin,and phenytoin combined with verapamil.Plasma and liver tissues were collected at different time after taking the drug in the plateau area.The concentration of phenytoin sodium in plasma was determined by UFLC-MS method.Changes in protein expression were detected by Western blot.Results The results of UFLC-MS showed that the AUC(0-t),AUC(0-∞),MRT(0-∞),MRT(0-∞),T_(1/2z),CL_(z)/F and V_(z)/F increased after P-gp agonist administration.After administration of P-gp inhibitor,AUC(0-t),AUC(0-∞),MRT(0-t),MRT(0-∞),T_(1/2z) decreased.HDAC5 was involved in the regulation of P-gp expression under high altitude hypoxia environment.When P-gp agonist and inhibitor were given,the expression of HDAC5 and P-gp showed the same trend.Conclusions The changes of P-gp transporter in liver affect the pharmacokinetics of P-gp substrate phenytoin under high altitude hypoxia environment,and the changes of P-gp are related to HDAC5.

关 键 词：高原低氧 P-GP 苯妥英钠 表观遗传学 HDAC5 药代动力学 

分 类 号：R-332[医药卫生] R339.54R341.27R341.32R845.22R969.1R971.6