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常用中药广藿香和胡黄连药物代谢动力学研究

The Pharmacokinetic Study of Chinese Traditional Medicine of Pogostemon Cablin (Blanco) Benth and Picrorhiza Kurroa Royle ex Benth

【作者】 杨甫传

【导师】 徐丽珍; 朱春燕; 齐云; 杨世林;

【作者基本信息】 中国协和医科大学 , 生药学, 2004, 博士

【摘要】 本文分两部,第一部分为广藿香醇及广藿香油中广藿香醇药物代谢动力学的研究;第二部分为胡黄连苷Ⅱ及胡黄连总苷中胡黄连苷Ⅱ药物代谢动力学的研究。 1 广藿香醇及广藿香油中广藿香醇药物代谢动力学研究 1.1 生物样品中广藿香醇定量分析方法的建立 首次建立了毛细管气相色谱测定生物样品中广藿香醇的方法,方法学研究表明,该方法稳定可靠,操作简便,线性范围宽,定量限达到25ng/mL,满足药物代谢动力学研究需要。 1.2 药物代谢动力学研究 分别研究了广藿香醇单体化合物及广藿香油中广藿香醇在大鼠、家兔及犬体内的药物代谢动力学过程,涉及静脉注射、口服及腹腔注射三种给药途径。 1.2.1 不同种属动物表现出的共性 广藿香醇及广藿香油中广藿香醇在不同种属动物体内的药物代谢动力学过程表现出一定的共性,这种共性可以认为是药物自身的属性。 (1) 线性动力学特征 研究表明,静脉注射给药,广藿香醇单体化合物及广藿香油中广藿香醇在大鼠、家兔及犬体内均表现出明显的线性动力学特征,即消除半衰期与剂量无关、血药浓度-时间曲线下面积与给药剂量成正比。口服给药,广藿香醇单体化合物在大鼠体内同样表现出半衰期与剂量无关、AUC与剂量成正比等线性动力学特征。但广藿香油中广藿香醇在大鼠体内的线性动力学特征不明星,主要表现为:随着剂量的增加,消除半衰期延长;AUC随剂量增加而增加,但增加幅度随剂量的增加而降低。 (2) 广藿香醇与广藿香油中广藿香醇药物代谢动力学行为的差异 研究表明,广藿香醇单体化合物与广藿香油中广藿香醇的药物代谢动力学行为显著不同,这种不同存在于不同种属的动物中、存在于不同的给药途径中。 消除半衰期 广藿香油中广藿香醇的消除半衰期明显长于广藿香醇单体化合物,这一特征不因给药途径、动物种属的改变而改变。可以认为,广藿香油中的其他成分与广藿香醇竞争被机体消除,使得广藿香油中广藿香醇的消除半衰期长于广藿香醇单体化合物。 AUC 静脉注射给药,广藿香油中广藿香醇的AUC明显高于广藿香醇单体化合物的AUC,这一特征在大鼠、家兔及犬等不同种属的动物中均表现明显,表明静脉注射给药,广藿香油中其他成分与广藿香醇有协同作用。 表观分布容积 研究表明,表观分布容积与给药途径有关,口服给药的表观分布容积>腹腔注射给药>静脉注射给药。表观分布容积还与药物的存在形式有关,广藿香醇单体化合物的表观分布容积明显低于广藿香油中广藿香醇的表观分布容积,这一特点在口服给药表现的尤为明显。

【Abstract】 Patchouli alcohol and patchouli oil extracted from Pogostemon cablin (Blanco) Benth. and picroside II and kurroa glucosides extracted from Picrorhiza kurroa Royle ex Benth. were used for pharmacokinetics study.A capillary gas chromatographic method was developed for the pharmacokinetic study of patchouli alcohol in the plasma, tissues, urine and dejection of rats. The patchouli alcohol in samples was extracted with ethyl acetate and eugenol was used as internal standard. The separation was carried out on a HP-5MS fused silica capillary column with flame ionization detector (FID) and high-purity nitrogen as carrier gas, utilizing programmed oven temperature. The linearity and repeatability of this method were satisfactory and its recovery was from 90% to 110% with relative standard deviation (RSD) less than 10%.The sensitive and simple high performance liquid chromatography method with UV detection was developed and validated for determining picroside II in the plasma, tissues, urine and dejection of rats. The sample pre-treatment procedure consists of deproteinization by addition of acetonitrile. The analysis was done on a Shimadzu VP-ODS column (250 mm × 4.6 mm i. d., 5 μm). The mobile phase consisted of acetonitrile and 0.1% acetic acid aqueous (v/v), at a rate of 1 mL/min. The linearity, repeatability and recovery of this method were satisfactory for determination picroside II.Patchouli alcohol showed linear pharmacokinetics in rats, rabbits and dogs, and the concentration-time data were consistent with the two-compartment open model after patchouli alcohol or patchouli oil i.v. administrated. The t1/2β of patchouli alcohol was less than that of patchouli alcohol in patchouli oil, and this suggested the elimination of patchouli alcohol in patchouli oil was affected by the other compounds.The bioavilability of patchouli alcohol or patchouli alcohol in patchouli oil was less than 40% and patchouli alcohol in patchouli oil was much less than that of patchouli alcohol, and this suggested the absorption of patchouli alcohol in patchouli oil was affected by the other compounds.Patchouli alcohol or patchouli alcohol in patchouli oil was mainly distributed in intestine, stomach, liver, spleen and kidney and it was also found in other tissues after i.v. administrated to

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