杜仲提取物多次给药后在正常大鼠和SHR模型体内的药动学比较研究

Pharmacokinetic comparison of active components in an Eucommia ulmoides extract by multiple administrations between normal and spontaneously hypertensive rats

目的研究杜仲提取物多次给药后松脂醇二葡萄糖苷((+)-pinoresinol di-O-β-D-glucopyr-anoside,PDG)、京尼平苷酸(genipinic acid,GA)、绿原酸(chlorogenic acid,CA)、原儿茶酸(protocatechuic acid,PCA)、新绿原酸(neochlorogenicacid,NCA)、隐绿原酸(cryptochlorogenic acid,CCA)和松脂醇单葡萄糖苷((+)-pinoresinol 4’-O-β-D-glucopyrano-side,PG)7个活性成分在正常大鼠和自发性高血压大鼠机体内的药代动力学差异。方法采用正常大鼠和自发性高血压大鼠为实验对象,以5.4 g/kg的给药剂量灌胃杜仲提取物,每天1次,连续7 d,比较杜仲提取物中的7个活性成分在正常大鼠与SHR模型体内的药代动力学和组织蓄积情况差异。结果药代动力学的研究结果发现,CCA和NCA在SHR模型体内的药动学参数与正常组比较无明显差异。在SHR模型组体内PDG的T_(1/2)为正常组的0.26倍;GA的T_(1/2)、T_(max)、AUC_(0-t)在SHR模型组中分别为正常组的2.20、0.04、0.50倍;PG在SHR模型组体内的T_(1/2)为正常组的0.55倍;PCA在SHR模型组内的T_(1/2)为正常组的2.04倍;CA的T_(1/2)、AUC_(0-t)分别为正常组的1.93、0.64倍。蓄积实验结果发现,GA等7种活性成分主要分布在胃、小肠、心、肝和肺中。除CCA外,CA、NCA、PCA、GA、PDG和PG在SHR模型体内与正常组相比,含量存在显著差异的组织器官数量分别为2~7个不等。结论自发性高血压病理状态下的机体能够显著改变杜仲降压活性成分在血浆中药动学行为以及组织中的蓄积情况,而对于需要长期服药的高血压患者而言,药物在体内的药动学行为尤为重要,本研究可为杜仲在临床上的长期使用剂量调整提供一定的参考。

Objective To investigate differences in pharmacokinetics and accumulation of seven bioactive constituents,namely(+)-pinoresinol di-O-β-D-glucopyr-anoside(PDG),genipinic acid(GA),chlorogenic acid(CA),protocatechuic acid(PCA),neochlorogenic acid(NCA),cryptochlorogenic acid(CCA)and(+)-pinoresinol 4’-O-β-D-glucopyrano-side(PG)in Eucommia ulmoides after multiple intragastric administrations between normal rats and spontaneously hypertensive rats(SHRs).Methods Normal rats and SHRs received intragastric Eucommia ulmoides extract at a dose of 5.4 g/(kg·d)for 7 consecutive days.Then,the pharmacokinetic parameters and tissue distribution were compared between normal rats and SHRs.Results Pharmacokinetic tests showed no obvious differences in all pharmacokinetic parameters of NCA and CCA between normal and model groups.The T_(1/2) value of PDG in SHRs was 0.26 times that of normal rats.In model group,the T_(1/2),T_(max) and AUC_(0-t) of GA were 2.20,0.04 and 0.50 times those of normal group,respectively.For model group,the T_(1/2) value of PG was 0.55 times that of normal group.Compared with normal rats,the T_(1/2) of PCA in SHRs was increased by 2.04 times.The T_(1/2) and AUC_(0-t) of CA in SHRs were 1.93 and 0.64 times of normal rats,respectively.Accumulation analysis showed that all representative active components were mainly distributed in the stomach,intestines,heart,liver and lungs.Except for CCA,the contents of the others in SHRs presented notable differences in tissues of two to seven compared with normal group.Conclusions The pharmacokinetics and accumulation of active anti-hypertensive components in Eucommia ulmoides extract after multiple administrations in rats were influenced remarkably by the pathological state of spontaneous hypertension.Moreover,it is important to learn about the pharmacokinetic characteristics of drugs for those who suffer from hypertension and need to take medicine persistently.This study provides a reference for clinical dosage adjustment of Eucommia ulmoides when used long-term.