HMS-01在小鼠体内的药动学研究

Pharmacokinetic study of HMS-01 in mice

目的研究HMS-01在小鼠体内的药动学,为后续研究、提供支持。方法采用液相色谱-串联质谱(LC-MS/MS)技术,建立灵敏、特异的测定血浆等生物样品中HMS-01浓度的分析方法,用建立的方法开展HMS-01在C57BL/6J小鼠体内药动学研究。分别对其进行了3个剂量单次灌胃给药、1个剂量单次静注给药的药动学研究,以获得基本药动学参数。结果小鼠药代动力学结果表明,HMS-01肠道吸收快,小鼠口服生物利用度中等(50%~70%)。HMS-01在小鼠体内的暴露水平(AUC和c_(max))随剂量的增加而增加,其中AUC随剂量的增加成线性相关。HMS-01静脉给药后,在小鼠体内的半衰期不长(约1 h);血浆清除率(CL_(tot,p))为2.8L/(h·kg),与小鼠肝血流量相当;表观分布容积(V_(SS))为5 L/kg,远大于小鼠总体液。雌雄小鼠经HMS-01口服30、60mg/kg,在AUC和F有显著差异(P<0.05),在c_(max)、AUC_(0−∞)、t_(1/2)、CL_(tot,p)、MRT、V_(SS)等参数上接近,均无显著差异。结论HMS-01在小鼠体内的药动学过程有性别差异,雌性小鼠的血药浓度时间曲线下面积、生物利用度均高于雄性。由于口服生物利用度尚可,可考虑通过口服给药途径对HMS-01治疗小鼠心衰的进一步的体内研究提供依据。

Objective To study the pharmacokinetics of HMS-01 in mice and provide support for subsequent studies.Methods Liquid chromatography-tandem mass spectrometry(LC-MS/MS)was used to establish a sensitive and specific method for the determination of the concentration of HMS-01 in plasma and other biological samples.The pharmacokinetics of HMS-01 in C57BL/6J mice were studied by the established method.To obtain the basic pharmacokinetic parameters,three doses of HMS-01 were given orally and one dose of HMS-01 was given intravenously.Results The pharmacokinetic results of mice showed that the intestinal absorption of HMS-01 was fast,the oral bioavailability of HMS-01 in mice was moderate(50%to 70%).The exposure levels(AUC and c_(max))of HMS-01 in mice increased with the increase of dosage,while the AUC was linearly correlated with the increase of dosage.After intravenous administration of HMS-01,the half-life period in mice was about 1 h which was not long.The plasma clearance rate(CL total.p)was 2.8 L/h·kg,which was similar to the hepatic blood flow of mice.The apparent volume of distribution(V SS)was 5 L/kg,which was much larger than the total mouse fluid.There were significant differences in AUC and F(P<0.05),but no significant differences in parameters such as c_(max),AUC_(0−∞),t_(1/2),CL_(tot,p),MRT,Vss in male and female mice which were given 30 and 60mg/kg HWS-01 orally.Conclusion The pharmacokinetic process of HMS-01 in mice showed gender differences,and the area under the curve of blood concentration time and bioavailability of female mice were higher than that of male mice.As oral bioavailability was reasonable,further in vivo studies on HMS-01 in mice with heart failure by oral administration could be considered to provide evidence.