大鼠口服有效及接近耐受剂量的菊花提取物后木犀草素与芹菜素的药动学研究

 目的 研究大鼠口服有效及接近耐受剂量的菊花提取物后，其主要效应成分（木犀草素和芹菜素的药动学，并考察其药动学参数与剂量间的关系。方法 20只SD雄性大鼠随机分成4组，分别灌胃100，200，400及12 000 mg·kg-1的菊花提取物，采集给药前及给药后72 h内不同时间点血浆，以HPLC测定血浆中木犀草素及芹菜素的浓度。采用DAS（V2.0软件，以非房室模型计算主要的药动学参数，包括：峰浓度（ρ_max、 血药浓度-时间曲线下面积（AUC、消除半衰期（t1/2、表观分布容积（Vd、 血浆清除率（CL等。 结果 大鼠灌胃菊花提取物，当剂量以1∶2∶4递增时（100～400 mg·kg-1，木犀草素和芹菜素的ρ_max分别以1.0∶2.0∶4.1及1.0∶2.4∶4.4递增，AUC分别以1.0∶2.1∶4.6及1.0∶2.0∶4.3递增；不同剂量间木犀草素和芹菜素的t1/2、CL、Vd无明显差异，两者的t1/2分别为7.75～8.93 h和6.51～7.05 h， CL分别为8.94～11.8和1.34～1.69 L·h·kg-1 ，Vd分别为43.0~55.2 L·kg-1和11.4～13.7 L·kg-1。当剂量由400增加到12 000 mg·kg-1时，木犀草素及芹菜素的ρ_max仅增加2.4和2.0倍，AUC仅增加6.4和3.1倍，但t1/2、CL、Vd显著增大，木犀草素的t1/2、CL及Vd分别为14.2 h、41.1 L·h·kg-1、858 L·kg-1，芹菜素的t1/2、CL及Vd分别为41.6 h、15.5 L·h·kg-1 、337 L·kg-1。结论 大鼠灌胃100～400 mg·kg-1菊花提取物，其效应成分木犀草素及芹菜素呈线性动力学特征，而剂量由400增加到12 000 mg·kg-1时，表现出非线性动力学特征。

Pharmacokinetics of Luteolin and Apigenin in Rats after Single Oral Administration of Chrysanthemum morifolium Extract at the Dose of Effectiveness and Approximating to the Maximal Tolerance

OBJECTIVE To evaluate the pharmacokinetics of luteolin and apigenin， the main effective components of Chrysanthemum morifolium extract (CME， and study the relationship between main pharmacokinetic parameters and dosage， under the series dosages of effectiveness and approximate to the maximal tolerance dose of CME by single oral administration to rats. METHODS 20 male SD rats were randomly allocated into 4 groups of 5 rats each， and received CME by gavage at the doses of 100， 200， 400， and 12 000 mg·kg-1， serial plasma samples were collected over 72 h before and after administration. Iuteolin and apigenin were analyzed by modified HPLC method. Pharmacokinetic parameters， including the peak concentrations (ρ_max， the areas under the concentration versus time curves (AUC， and the elimination half life (t1/2， the plasma clearance (CL， the apparent volume of distribution (Vd were evaluated by software DAS (V2.0 with non-compartmental method. RESULTS Within 100~400 mg·kg-1， as the dose of CME increased in the ratio of 1∶2∶4， the ρ_max of luteolin and apigenin increased in the proportion of 1.0∶2.0∶4.1 and 1.0∶2.4∶4.4， the AUC increased in 1.0∶2.1∶4.6 and 1.0∶2.0∶4.3，whereas the other pharmacokinetic parameters did not change significantly among the different dose groups. And of luteolin and apigenin was as follows t_1/2 7.75~8.93 h and 6.51~7.05 h， CL 8.94~11.8 and 1.34~1.69 L·h·kg-1，Vd 43.0~55.2 L·kg-1 and 11.4~13.7 L·kg-1， respectively. However， as the dose increased from 400 to 12 000 mg·kg-1， the ρ_max of luteolin and apigenin increased by 2.4 and 2.0 times， and the AUC increased by 6.4 and 3.1 times， respectively， while the t1/2， CL， Vd increased obviously compared with the 400 mg·kg-1 group. CONCLUSION The pharmacokinetic characteristics of luteolin and apigenin in rats were linear over the CME dose range of 100-400 mg·kg-1， and nonlinear over the dose range of 400-12 000 mg·kg-1.