青蒿琥酯自微乳在大鼠体内的药动学研究

Pharmacokinetics of Artesunate self-microemulsion in rats

关键词:  青蒿琥酯  自微乳  药动学  LC-MS/MS

Key words:  artesunate  self-microemulsion  pharmacokinetic  LC-MS/MS

摘要:

目的 建立大鼠血浆中青蒿琥酯的HPLC-MS/MS测定方法，并研究青蒿琥酯自微乳在大鼠体内的药动学特征。方法 12只SD大鼠随机分为2组，单剂量分别灌胃（50 mg·kg^-1）青蒿琥酯自微乳和青蒿琥酯原料药，以格列吡嗪为内标，用LC-MS/MS测定给药后血浆中的药物浓度，并计算药动学参数。结果 青蒿琥酯血浆样品的线性范围为1.0~1 000.0 ng·mL^-1，回归方程为A=294.74C-439.33（r=0.999 6），定量下限为1.0 ng·mL^-1。日内、日间变异系数（RSD）均<10%，符合生物样品的分析要求。青蒿琥酯原料药和青蒿琥酯自微乳的药动学参数C_max、t_1/2和AUC_0→t分别为：（87.6±8.80）ng·mL^-1，（1.88±0.33）h和（43.3±1.74）h·ng·mL^-1；（421±41.6）ng·mL^-1，（1.48±0.17）h和（282±17.7）h·ng·mL^-1。其中，C_max和AUC_0→t存在显著性差异（p<0.01）。结论 该方法简便灵敏，可用于血浆中青蒿琥酯的含量测定，经灌胃给药后，与原料药比较，青蒿琥酯自微乳能显著提高生物利用度。

Abstract:

OBJECTIVE To establish a method for determining the plasma concentration of artesunate in rat with LC-MS/MS, and study the pharmacokinetic parameters of artesunate self-microemulsion in rat. METHODS Twelve SD rats were randomly divided into two groups, which were gavaged with a single dose of artesunate self-microemulsion and artesunate API at the concentration of 50 mg·kg^-1. Afterwards, the drug plasma concentrations were determined by LC-MS/MS with glipizide as an internal standard, and pharmacokinetic parameters were calculated as well. RESULTS The linear ranges of artesunate was from 1.0 to 1 000 ng·mL^-1 with a regression equation:A=294.74C-439.33(r=0.999 6), and the limit of quantitation was 1.0 ng·mL^-1. The intraday and inter-day variable coefficients were both <10%, which met the requirements of biological sample analyses. The C_max, t_1/2and AUC_0→t values of artesunate self-microemulsion were (421±41.6)ng·mL^-1,(1.48±0.17)h and (282±17.7)h·ng·mL^-1 while with values of (87.6±8.80)ng·mL^-1, (1.88±0.33)h and (43.3±1.74)h·ng·mL^-1for artesunate API. CONCLUSION The method for evaluating these pharmacokinetic parameters is simple and sensitive, which can be used for determining the content of artesunate in plasma. Besides, the bioavailability of artesunate self-microemulsion in rats is significantly improved after gavage administration compared to that of the artesunate API.