不同粒径阿瑞匹坦大鼠药代动力学比较

Pharmacokinetics study of aprepitant with different particle size in rat

目的建立检测大鼠血浆中阿瑞匹坦的HPLC法,并应用于大鼠体内药代动力学研究。方法血浆样品用液液萃取法。色谱柱为Agilent Eclipse XDB C18(150 mm×4.6 mm,5μm);检测波长为210 nm,流动相为水相(3.4 g磷酸二氢钾于1000 ml水中,磷酸调pH为3.0)-乙腈(55∶45),流速1 ml/min。将建立的分析方法应用于大鼠静注和口服3种粒径阿瑞匹坦(20、1和0.24μm)的药代动力学研究。结果阿瑞匹坦在0.1～5μg/ml和5～60μg/ml范围内线性关系良好(r分别为0.9980和0.9999);定量限为0.1μg/ml,方法的回收率≥70%,日内、日间精密度和准确度符合生物样品检测的要求。大鼠静注阿瑞匹坦20 mg/kg后,消除半衰期为6.70 h,AUC为27.30 mg.h/L。大鼠口服3种粒径阿瑞匹坦150 mg/kg后,禁食条件下的生物利用度分别为33.3%、47.6%和68.2%,进食条件下分别为59.6%、57.7%和64.9%。结论本实验建立了操作简便、准确、快速的定量检测血浆中阿瑞匹坦的HPLC法,可用于阿瑞匹坦的大鼠药代动力学和生物利用度研究。与微米制剂比较,纳米制剂不仅提高了生物利用度,而且消除了食物效应。

Objective To develop and validate a HPLC method for quantitative analysis of aprepitant in rat plasma,and to investigate its pharmacokinetics in rats.Methods The plasma samples were treated with liquid-liquid extraction.An Agilent Eclipse XDB C18 column（150 mm × 4.6 mm,5 μm） with UV detection at 210 nm,and aqueous phase（3.4 g potassium dihydrogen phosphate in 1000 ml water,pH adjusted to 3.0 with phosphoric acid）-acetonitrile（55∶ 45） as the mobile phase were used.The flow rate was 1.0 ml / min.The method was applied to pharmacokinetics study of aprepitant by intravenous injection and oral administration of three kinds of particle sizes（20,1 and 0.24 μm） in rats.Results A good linearity was obtained over the concentration range of 0.1-5 μg / ml and 5-60 μg / ml for aprepitant（r = 0.9980;r = 0.9999）,with the limit of quantification at 0.1μg / ml.The recovery of aprepitant was greater than 70%.The precision and the accuracy met the requirements of biological sample assay.The half-life and AUC were 6.7 h and 27.30 mg.h / L after a single iv（20 mg / kg） of aprepitant to rats.After oral（150 mg / kg） administrated aprepitant of three kinds of particle sizes,the bioavailability of rat under fasted conditions and fed conditions was 33.3%,47.6%,68.2% and 59.6%,57.7%,64.9%,respectively.Conclusion The results of the study show that the HPLC method is simple,rapid and accurate.It is suitable for the in vivo pharmacokinetics and bioavailability study of aprepitant in rats.Compared with the conventional micronized formulation,the nanoparticle formulation may not only enhance bioavailability but also eliminate food effect on absorption.