黄芪汤对大鼠体内恩替卡韦药动学的影响

Effect of Huangqi decoction on entecavir pharmacokinetics in rat plasma

恩替卡韦（ETV）是一线抗乙肝病毒（HBV）药物,黄芪汤（HQD）临床上对肝硬化有改善效应,两者可合用治疗乙肝肝硬化患者。本文建立了超高效液相色谱-线性离子阱-静电场轨道阱组合质谱法（UHPLC-LTQOrbitrap）测定大鼠血浆中恩替卡韦浓度,方法学考察表明恩替卡韦在0.100-20.0 ng·m L-1浓度内线性关系良好,符合生物样本测定要求。SD大鼠随机分成6组,有单次、多次给药,再分别分为单用恩替卡韦组（ETV组）、恩替卡韦与黄芪汤同时给药组（ETV-HQD组）和灌服恩替卡韦2 h后再给药黄芪汤组（ETV-HQD-2h组）,采用建立的UHPLC-LTQ-Orbitrap法测定恩替卡韦浓度。与ETV组相比,ETV-HQD组中恩替卡韦C_（max）降低,t_（max）延长,AUC0–t减少。ETV-HQD-2h组中黄芪汤与恩替卡韦间隔2 h给药对恩替卡韦药动学行为无显著影响。外翻肠囊实验发现,黄芪汤阻碍了恩替卡韦在小肠黏膜表面的吸收。结果表明,黄芪汤与恩替卡韦同时给药可减少恩替卡韦的吸收。

Entecavir （ETV）, a guanosine nucleotide antiviral agent with activity against hepatitis B virus （HBV） and Huangqi decoction （HQD） that exerts significant therapeutic effects in liver cirrhosis are used as an effective drug combination in the treatment of liver cirrhosis with HBV. Therefore, this study was designed to assess the effect of HQD on ETV pharmacokinetics in rat plasma. Spraque-Dawley （SD） rats were randomized into single- and 7-day-dose experimental groups. The ETV and ETV-HQD groups were administered ETV and a simultaneous combination of ETV and HQD, respectively while the ETV-HQD-2h group received HQD 2 h after ETV treatment, all administered via intragastric （i.g.） gavage. A rapid, sensitive, and efficient ultra-high- performance liquid chromatography-linear trap quadrupole （UHPLC-LTQ）-Orbitrap method was developed and validated to determine ETV in rat plasma from blood samples collected at different time points following treatment. The linearity, accuracy, precision, recovery, matrix effects and stability of ETV were all satisfactory. The ETV-HQD group exhibited a decrease in the maximum plasma concentration （Cmax）, and a delay in time to achieve Cmax （tmax） following single- and multi-dose administrations, and decreased area under the concentration- time curve （AUC0-1） following single dosing. ETV pharmacokinetics did not change significantly between the ETV and ETV-HQD-2h groups. In vitro everted intestinal sac models experiments indicated that HQDdecreased the absorption of ETV. HQD prevented ETV from accessing the intestinal mucosa epithelial surface, thereby decreasing its absorption in rats.