汉黄芩素-苦豆碱共晶在大鼠体内的药代动力学研究

Pharmacokinetics of wogonin-aloperine cocrystal in rats

药物共晶是改善药物理化性质和生物学特性的前沿技术,但目前关于药物共晶体内代谢的研究较少。本文在前期制备汉黄芩素-苦豆碱共晶的基础上,进一步研究汉黄芩素药物共晶在正常大鼠体内的药代动力学。首先,建立超高效液相色谱-串联质谱方法(ultra-performanceliquidchromatography-tandemmass spectrometry,UPLC-MS/MS)同时测定大鼠血浆中汉黄芩素及其代谢产物汉黄芩苷含量,并进行方法学考察;将该方法应用于汉黄芩素-苦豆碱共晶在大鼠体内的药代动力学研究。结果显示,汉黄芩素及其代谢产物汉黄芩苷在1~800ng·mL^(-1)内线性关系良好,在此范围内的精密度、准确度、基质效应及稳定性考察均符合生物分析要求;相较于汉黄芩素直接给药,以共晶形式给药后,大鼠体内汉黄芩素及其代谢产物汉黄芩苷的C_(max)分别提高至7.44倍和9.15倍,AUC_(0-t)提高至1.67倍和3.72倍,汉黄芩素口服生物利用度提高为187.66%。汉黄芩素-苦豆碱共晶可显著提高汉黄芩素及其代谢产物汉黄芩苷的C_(max)、AUC及口服生物利用度,为汉黄芩素的临床应用提供了新思路。本研究经北京中医药大学实验动物伦理审查委员会批准(批准编号为:BUCM-2023032307-1148)。

Pharmaceutical cocrystals is an advanced technology to improve the physicochemical and biological properties of drugs.However,there are few studies on the in vivo metabolism of pharmaceutical cocrystals.In this study,the pharmacokinetics of wogonin cocrystal in normal rats was further studied on the basis of the previous preparation of wogonin-aloperine cocrystal.Firstly,an ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)method was established for simultaneous determination of wogonin and its metabolite wogonoside in rat plasma,and to investigate the methodology.The method was applied to the pharmacokinetic study of wogonin-aloperine cocrystal(Wog-Alop)in rats.The results showed that wogonin and its metabolite wogonoside had a good linear relationship in the range of 1-800 ng·mL^(-1),and the precision,accuracy,matrix effect and stability in this range met the requirements of biological analysis.Compared with direct administration of wogonin,the C_(max) of wogonin and its metabolite in rats increased to 7.44-fold and 9.15-fold,AUC_(0-t),increased to 1.67-fold and 3.72-fold,and oral bioavailability of wogonin increased to 187.66%after cocrystal administration.Wog-Alop cocrystal can significantly improve the C_(max) AUC,and oral bioavailability of wogonin and its metabolite,which provides a new perspective for the clinical application of wogonin.This study was approved by the Experimental Animal Ethics Review Committee of Beijing University of Chinese Medicine(approval number:BUCM-2023032307-1148).