3TC-PA的体外稳定性及大鼠体内药代动力学研究  

Study on the Stability in Vitro and Pharmaco-kinetics of 3TC-PA in Rats

作　　者：罗萍 唐兰如 王俊俊[2] 陈勇[2] 苗潇磊 LUO Ping;CHEN Yong;MIAO Xiao-lei(School of Pharmacy,Xianning Medical College,Hubei University of Science and Technology,Xianning Hubei 437100,China)

机构地区：[1]湖北科技学院医学部药学院,湖北咸宁437100 [2]湖北大学中医药生物技术湖北省重点实验室/药物高通量药物筛选技术国家地方联合工程研究中心/生物催化与酶工程国家重点实验室

出　　处：《湖北科技学院学报（医学版）》2023年第4期285-291,297,共8页Journal of Hubei University of Science and Technology(Medical Sciences)

基　　金：药物高通量筛选技术国家地方联合工程研究中心开放课题基金(K20201006);湖北科技学院博士启动项目基金(BK201810);湖北科技学院校内科研发展基金项目附属第二医院专项资助(2021LCY003)。

摘　　要：目的研究化合物拉米夫定-原儿茶酸(3TC-PA)的体外稳定性以及在大鼠体内的药代动力学特征。方法HPLC法考察3TC-PA在不同pH(1.40、4.00、6.80、6.86、7.80)缓冲溶液,人工模拟胃、肠液,大鼠胃、肠内容物,全血和肝匀浆中的稳定性。SD大鼠单次灌胃3TC-PA(15.26mg/kg),LC-MS/MS法检测给药5、10、15、30、45、60、90、120、240、360min后血浆中3TC-PA的浓度,计算药代动力学参数。LC-MS/MS法检测肝、肾组织中3TC-PA的浓度。结果3TC-PA在中性、碱性条件下和人工胃液、人工肠液、大鼠肠内容物、全血中稳定性良好;在酸性条件下8h后开始分解;在大鼠胃内容物和肝匀浆中仅6h之后有少量分解。3TC-PA在大鼠体内的主要药动学参数如下:AUC0-t为5858.39μg/(L·min),AUC0-∞为5986.45μg/(L·min),T_(max)为15min,Cmax为91.63μg/L,t_(1/2z)为68.12min;给药后6min即可在大鼠肝、肾组织中检测到,15min时含量最高,各时间点3TC-PA在肝脏的暴露量高于肾脏中。结论3TC-PA体外稳定性良好;在大鼠体内吸收和消除迅速,能够快速分布至肝、肾组织中。Objective To investigate the stability in vitro and pharmacokinetic profile of compound 3TC-PA in rats.Methods The stability of 3TC-PA in buffered solutions of different pH(1.40,4.00,6.80,6.86,7.80),artificial simulated gastric and intestinal fluids,rat gastric and intestinal contents,blood and liver homogenates were investigated by HPLC.After a single gavage of 3TC-PA(15.26 mg/kg)to SD rats,the plasma concentrations of 3TC-PA were determined by LCMS/MS 5,10,15,30,45,60,90,120,240 and 360 min after administration and the pharmacokinetic parameters were calculated.Additionally,concentrations of 3TC-PA within liver and kidney tissues were determined using LCMS/MS.Results 3TC-PA exhibited stable in neutral,alkaline conditions,artificial gastric and intestinal fluids,rat intestinal contents and blood.However,decomposition began after 8 h under acidic conditions.In the stomach contents and liver homogenate of rat,there was only a small amount of breakdown after 6 h.The key pharmacokinetic parameters of 3TC-PA in rats were as follows:AUC0-t was 5858.39μg/(L·min),AUC0-∞was 5986.45μg/(L·min),T_(max)was 15min,Cmax was 91.63μg/L and t_(1/2z)was 68.12min.3TC-PA was detected in rat liver and kidney tissues 6 min post-administration,peaking at 15 min.3TC-PA exposure was higher in the liver than in the kidney at all time points.Conclusion 3TC-PA is stable in vitro.It is rapidly absorbed and eliminated in rat,demonstrating swift distribution to liver and kidney tissues.

关 键 词：拉米夫定 原儿茶酸 药代动力学 体外稳定性 慢性乙型肝炎 

分 类 号：R96[医药卫生—药理学]