黄蜀葵花中4种黄酮类成分体内整合药动学研究

目的建立黄蜀葵花提取物中4种黄酮类成分在大鼠血浆中的HPLC测定方法,考察4种成分在大鼠体内各自的和整合的药动学特性,并分别计算绝对生物利用度。方法大鼠ig和iv给予黄蜀葵花提取物浸膏后,采用HPLC法,测定其中4种黄酮类成分金丝桃苷、异槲皮苷、棉皮素-8-葡萄糖醛酸、槲皮素-3′-葡萄糖苷不同时间间隔的血药浓度,运用DAS2.0药动学程序计算各成分的药动学参数,利用各成分曲线下面积(AUC0-∞)百分率作为自定义权重系数,计算黄蜀葵花提取物大鼠体内综合血药浓度,并建立整合药动学研究模型,进一步估算整合药动学参数。根据药时曲线的AUC面积计算绝对生物利用度。结果4种黄酮类成分的线性范围为0.1~8μg/mL(r0.99),定量限为0.1μg/mL,回收率在70%以上,日内、日间RSD均低于15%。ig或iv给药后4种成分的药动学参数差异很大,4种成分及整合后绝对生物利用度分别是:12.9%、10.8%、2.2%、10.2%、5.9%。结论该法简便、灵敏、准确,为黄蜀葵花的生物利用度研究以及建立临床合理的给药方案奠定了基础。黄蜀葵花中4种黄酮类成分在大鼠体内能快速分布并消除,两种给药途径的体内药动学过程不同,基于4种成分的AUC0-∞自定义权重系数的整合药动学研究模型符合经典药动学模型特征,所获参数能够最大程度上表征中药的整体处置规律,为建立符合中医药特点的中药多组分整合药动学新方法作一尝试。

In vivo integrated pharmacokinetics of four flavonoids of Abelmoschus manihot extract in rats

Objective To establish an HPLC method for determination of four flavonoids concentration in blood plasma and investigate their pharmacokinetics and bioavailability after ig and iv administration of extracts in corolla of Abelmoschus manihot (EAM) in rats. Methods An HPLC-UV method was estab-lished and validated for the simultaneous determination of flavonoids, hyperin, isoquercitrin, hibifolin, quercetin-3'-O-glucoside in rat plasma. Pharmacokinetic parameters of each compound were calculated using DAS software. A novel approach of self-defined weighting coefficient based on the area under the curve from zero to infinity (AUC_(0-∞)) had been created to obtain the holistic pharmacokinetic profiles of EAM. The integrated pharmacokinetic parameters of EAM were then calculated from both typical com-partment and non-compartmental model analysis. The absolute bioavailabilities were calculated based on the (AUC_(0-∞）) values. Results A good linearity was obtained at 0. 1-8μg/mL of flavonoids in rat plasma with r > 0.99. The quantitive restriction was 0. 1 μg/mL, the recovery rate was over 70%. The RSD of intra- and inter-day was less than 15 %. The pharmacokinetic parameters of flavonoids were different from each other after ig and iv administration. The absolute bioavailability of flavonoids were 12.9%, 10.8%, 2.2%, 10.2% and 5.9%, respectively. Conclusion The method is sensitive, specific, accurate, and is not only useful for guiding the bioavailability study on the corolla of A. Manihot, but also for establishing a reasonable clinical dosage program. The four flavonols in the corolla of A. Manihot can be rapidly dis-tributed and eliminated in rats, the pharmacokinetics of two routes of administration are different. A novel integrated pharmacokinetic approach to describing the holistic pharmacokinetic properties of Chinese mate-ria medica has been successfully developed and validated using four flavonols of A. Manihot as a model herbal medicine. This study would be a new try for guiding the holistic pharmacokinetic study in consis-tence with the intrinsic theory and characteristics of traditional Chinese medicine.