喹硫平和达泊西汀在大鼠体内外的代谢情况及药代动力学作用  

Effects of quetiapine and dapoxetine on the expression of liver microsomal associated proteins in vitro and in vivo of rats and their pharmacokinetic action

作　　者：胡建[1] 李军[2] 张锐[3] ZU Jian;LI Jun;ZHANG Rui(Department of Pharmacy,Sichuan Demobilized Veterans Hospital,Sichuan,Chongzhou 611230,China)

机构地区：[1]四川省复员退伍军人医院药剂科,四川省崇州市611230 [2]四川省复员退伍军人医院精神科,四川省崇州市611230 [3]成都大学附属医院

出　　处：《河北医药》2019年第15期2245-2249,共5页Hebei Medical Journal

摘　　要：目的探讨喹硫平对达泊西汀的药代动力学影响,为临床喹硫平与达泊西丁的联合用药提供科学参考。方法体外取肝微粒体与达泊西丁共同孵育,以达泊西汀浓度为指标,采用高效液相色谱法(HPLC),检测不同浓度下喹硫平对达泊西汀代谢率的影响;体内代谢实验中将Wistar大鼠随机分为空白组(0.9%氯化钠溶液组)和喹硫平组(浓度为0.5mg/ml),连续灌胃1周,末次灌胃1h后给大鼠灌胃达泊西汀,之后24h内,于0、10、30min,1、2、4、8、16、24h对大鼠进行尾静脉采血,离心,HPLC检测达泊西汀浓度,绘制血药浓度曲线,将大鼠处死后取肝脏及小肠,采用HE染色、免疫组织化学染色法观察组织形态及蛋白表达,用WB法检测肝脏CYP3A1同工酶以及5羟色胺转运蛋白(5-HTT)的表达情况。结果达泊西汀在10~800ng/ml浓度范围内线性关系很好。体外代谢精密度RSD为2.01%~3.25%,回收率为98.52%~102.17%,RSD为2.32%~3.05%。体内代谢精密度RSD为3.13%~5.51%,回收率为99.62%~103.56%,RSD为2.23%~4.57%。体外结果表明,与空白组比较,不同浓度喹硫平对达泊西汀代谢率的影响差异无统计学意义(P>0.05),高浓度喹硫平对达泊西汀代谢具有抑制趋势,喹硫平浓度越高,达泊西汀浓度相对越高。体内代谢结果表明,与空白组比较,不同时间点喹硫平对血清内达泊西汀代谢率的影响并差异无统计学意义(P>0.05);与空白组比较,实验组HE染色、免疫组织化学染色、蛋白表达量均差异无统计学意义(P>0.05)。结论喹硫平对达泊西汀体内外代谢均无明显抑制作用,两药联用,不会影响达泊西汀发挥正常的药理作用。Objective To explore the effects of quetiapine on pharmacokinetics of dapoxetine,in order to provide scientific reference for the drug combination application of quetiapine and dapoxetine in clinical practice.Methods The liver microsomes of rats were taken in vitro for co-incubation with dapoxetine,and the effects of quetiapine on the metabolic rate of dapoxetine at different concentrations were detected by high performance liquid chromatography(HPLC).In vivo metabolism experiment,the Wistar rats were randomly divided into blank group(0.9%sodium chloride solution group)and quetiapine group(the concentration of 0.5mg/ml).The rats in each group were given the drugs at 10ml/kg by gavage for one week.At one hour after the last intragastric administration,the rats were given dapoxetine by gavage,then the blood was collected from tail vein at 0min,10min,30min,1h,2h,4h,8h,16h,24h.The dapoxetine levels were detected by HPLC,the blood drug concentration curve was drawn.After the rats were sacrificed,the liver and small intestine were taken out,and the histological morphous and protein expression were observed by HE staining and immunohistochemical staining.Moreover the expression levels of CYP3A1 isozyme and 5-hydroxytryptamine(5-HT)transporter in liver were detected by Western Blot.Results There was a good linear correlation at the concentration of 10~800ng/ml dapoxetine.In vitro experiment,the metabolism accuracy RSD was 2.01%~3.25%,the coefficient of recovery was 98.52%~102.17%,RSD was 2.32%~3.05%.In vivo experiment,the metabolism accuracy RSD was 3.13%~5.51%,the coefficient of recovery was 99.62%~103.56%,RSD was 2.23%~4.57%.The research results in vitro showed that there were no significant differences in the effects of different concentrations of quetiapine on the dapoxetine metabolism rate between blank group and quetiapine group(P>0.05).The high concentration of quetiapine had a inhibition tendency on the metabolism of dapoxetine.The higher the concentration of quetiapine,the higher the concentration of dapoxetine.

关 键 词：喹硫平 达泊西汀 药代动力学 肝微粒体 蛋白表达 

分 类 号：R969.1[医药卫生—药理学]