牛蒡苷元药物动力学研究

【作者】 吕佳；

【导师】 康廷国； 赵中振；

【作者基本信息】 辽宁中医学院 ， 生药学， 2002， 硕士

【摘要】 牛蒡苷元具有显著的抗菌，抗病毒，抗肿瘤，抗PAF受体的作用，有很高的新药开发价值。因此研究牛蒡苷元的药代动力学对于牛蒡苷元的开发利用有重要意义。本研究以牛蒡子（Fructus Arctii）为原料，采用化学和层析方法制备活性成分牛蒡苷元。建立了生物样品中牛蒡苷元含量测定方法，在1.916×10^-4-4.79×10^-2μg范围内，色谱峰面积与牛蒡苷元的进样量（μg）呈良好线性关系，回归方程为：Y=1119986X+1508.8，r=O.9993，方法学考察符合生物样品测定要求；对牛蒡苷元小鼠胃肠道吸收、家兔静脉注射、灌胃牛蒡苷元的药物动力学特征以及牛蒡苷元在大鼠体内分布作了研究，实验结果表明牛蒡苷元在胃肠道内较为稳定，转化、破坏较少。牛蒡苷元的胃肠道吸收为一级动力学过程，吸收速度常数：Ka=O.642h^-1；吸收半衰期：T_1／2（h）=1.1h；家兔静注不同剂量牛蒡苷元时，各剂量的T_1／2等主要动力学参数十分接近，且AUC随剂量增加而成比例增加，说明牛蒡苷元的消除为线性动力学；家兔静脉注射牛蒡苷元，其药物动力学行为符合单室模型，消除半衰期t_1／2（k_e）为52.16473min，AUC为205.66782（ug／ml）×min，消除速度常数Ke（l／min）为0.01329。家兔灌胃牛蒡苷元，其药物动力学行为符合单室一级吸收模型，消除速度常数K_e为0.8888（1／hr），Ka为1.4584（1／hr），吸收半衰期t_1／2（Ka）为0.47527hr，消除半衰期t（1／2）（Ke）为0.77983h。T（peak）为1.56hr；在实验条件下，家兔灌胃牛蒡苷元的绝对生物利用度为9.5％。大鼠灌胃牛蒡苷元后24小时从尿中排出原形物累积量相当于给药量的0.423％，且大都于18h内排出。给药后24小时从粪中排出原形物累积量相当于给药量的0.11％；分布实验表明，牛蒡苷元在大鼠体内分布广泛，在肝、肺中分布浓度较高，其次为心、脾、肾等。血浆蛋白结合率实验表明，牛蒡苷元与大鼠血浆蛋白平均结合率为：78.3％。 本文首次研究了牛蒡苷元的药物动力学特征，本实验的研究结果可对牛蒡苷元的深入研究及新药开发打下一定基础。对研制使用方便、高效的剂型，制定科学、合理的给药方案等具有一定的参考价值。更多还原

【Abstract】 Arctigenin has great value to be developed into a new medicine for its obviously anti-virus, anti-cancer, calcium antagonist action and PAF(platelet activating factor) antagonist activity. The pharmacokinetics study of Arctigenin is an important base for its new medicine developing. In this study, Arctigenin, the active ingredients in Fructus Arctii were prepared by chemical and chromatographic methods.A method was established for the determination of Arctigenin in biological-samples by HPLC in this paper. The calibration curve in plasma was liner in the range from 1. 916X10-1-4. 79X10-2ug with r=0. 9993, and the detection limit of this method was 9. 58Xl(Tu g. The extraction recoveries of all samples were over 70%, the relative standard deviations for within-day and between-day were below 8%. The methodological test indicated that the method was simple and good enough to be used in pharmacokinetic study of Arctigenin samples in biological samples.The absorption of Arctigenin through mice gastro-intestinal tract was studied in this report. The result indicated that Arctigenin was relatively stable in gastro-intestinal tract of mices and the absorption fit in first-order absorption with absorptive rate constant Ka=0. 642h-1 and absorptive half life T1/2=l.1h.The pharmacokinetics, bioavailability and excretion of Arctigenin were reported in this paper. The result showed that the concentration-time curves of Arctigenin after iv of 6,8, l0mg/kg to rabbits fit in a one-compartment model and the elimination of arctigenin from plasma was in according with linear kinetics. The concentration-time curve of Arctigenin fit in a one-compartment model after iv to rabbits with t1/2(ke)=52. 2min, Ke(l/min)=0. 01329, AUC=205. 66782. The concentration-time curve of Arctigenin after i. g into rabbits fits in one-compartment model with one order absorption. Ka=l. 4584 (1/h), Ke=0. 8888 (1/h), t1/2(Ka)=0. 48h, t1/2(Ke)=0. 78h, T(peak)=l. 56h. The absolute bioavailability of Arctigenin after i. g to rabbits is 9.5%. The 24h accumulated excreted amount from urine after i. g was 0. 423% and most amount of Arctgenin was excreted within 18h after i. g. The 24h accumulated excreted amount from feces after ig was 0. 11%.Arctigenin distribution in rats was studied and the result indicated that concentration of Arctigenin was the higher in liver and lung, followed by heart, spleen and kidney. Arctigenin was not found in brain tissues and this indicated that Arctigenin could not pass blood-brain barrier. The average plasma-protein binding percentage is 78.3% in rat.更多还原