摘要
槲寄生为桑寄生科植物槲寄生的干燥带叶茎枝，本研究以其为研究对象，对药材的化学成分，质量控制和体内药物动力学过程进行研究，并分析了槲寄生中活性成分高圣草素-7-O-β-D-葡萄糖苷的药代动力学过程。
采用各种色谱技术从槲寄生中分离得到18个化合物，鉴定了15个。其中1个新化合物：1，7-二(4-羟基苯基)-庚烷-1，4-二烯-3-酮；1个新天然产物：5-羟基-3，7，3′-三甲氧基黄酮-4′-O-β-D-葡萄糖苷；1个槲寄生属植物首次分离：5，7，4′-三羟基-3，3′-二甲氧基黄酮。
采用高效液相色谱法和毛细管气相色谱法，对不同产地和不同寄主的槲寄生进行指纹图谱研究。用系统聚类分析法将药材分类，结合分类结果，以相似度软件生成指纹图谱共有模式，分别以夹角余弦、相关系数为测度，计算样品与共有模式之间的相似度。研究发现不同寄主的槲寄生药材和不同产地的槲寄生药材指纹图谱相似度较好，但寄主与槲寄生之间指纹图谱存在较大差异，初步推断槲寄生药材指纹图谱受寄主的影响较小。槲寄生的HPLC指纹图谱和GC指纹图谱分别反映了药材不同化学部位的信息，对未知样品进行研究时，应根据临床应用而有所侧重。
对槲寄生主要有效成分进行了定性定量分析。采用HPLC-UV方法，在280 nm波长条件下同时定量分析5个有效成分：紫丁香苷、高圣草素-7-O-β-D-芹菜糖(1→5)-β-D-芹菜糖(1→2)-β-D-葡萄糖苷、高圣草素-7-O-β-D-芹菜糖(1→2)-β-D-葡萄糖苷、高圣草素-7-O-β-D-葡萄糖苷和高圣草素，并应用于不同产地、不同寄主的槲寄生药材测定，结果发现不同产地的药材含量差异较大，槲寄生叶中5个成分的含量普遍高于茎枝中的。所建立的分析方法简单、准确，为槲寄生药材的质量控制提供了科学依据。采用气相色谱质谱联用法和已知物对照法对槲寄生的挥发油进行分析，鉴定了22个化学成分，为槲寄生挥发性成分的进一步研究提供依据。
高圣草素-7-O-β-D-葡萄糖苷为槲寄生的有效成分，由于其较好的药理活性受到人们广泛关注。本研究以高圣草素-7-O-β-D-葡萄糖苷单体为研究对象，对其在大鼠体内的药代动力学过程进行研究。以香兰素为内标，建立了测定大鼠血浆中高圣草素-7-O-β-D-葡萄糖苷的HPLC分析方法。色谱柱Diamonsil C_(18)(200mm×4.6mm，I．D．5μm)，流动相为甲醇-0.5％冰醋酸水溶液(45∶55，v／v)。日内和日间精密度(RSD)小于9.7％，准确度(RE)在-0.8％～5.4％之间范围内，提取回收率大于70.0％。利用所建立的分析方法对高圣草素-7-O-β-D-葡萄糖苷在大鼠体内的药动学行为进行研究，高圣草素-7-O-β-D-葡萄糖苷消除速率常数Ke为0.73 h~(-1)，血浆中的半衰期t_(1／2)为1.56 h左右，AUC_(0～t)、AUC_(0～∞)分别为7.16、7.82μg·h／ml。对大鼠尿中代谢产物进行鉴定，发现高圣草素-7-O-β-D-葡萄糖苷进入体内后被代谢成苷元高圣草素。采用HPLC-MS法，以双氢杨梅黄素为内标，色谱柱为Luna C_(18)(150 mm×4.6 mm，I．D．5μm)，流动相为甲醇-0.1％甲酸水溶液(70∶30，v／v)，对高圣草素-7-O-β-D-葡萄糖苷及其代谢物高圣草素在大鼠体内的分布和排泄进行了研究。大鼠静脉注射高圣草素-7-O-β-D-葡萄糖苷后，迅速分布于各组织器官，小肠和肝脏浓度最高，分布量随时间的延长而下降。高圣草素-7-O-β-D-葡萄糖苷代谢物高圣草素，在多数组织中均能被检测到，其中肾脏的浓度最高。给药后60 h有相当于给药量的11.06％的原形药物和相当于给药量6.89％的苷元经尿液排泄。
建立了同时测定大鼠血浆中紫丁香苷、高圣草素-7-O-β-D-芹菜糖(1→5)-β-D-芹菜糖(1→2)-β-D-葡萄糖苷、高圣草素-7-O-β-D-芹菜糖(1→2)-β-D-葡萄糖苷和高圣草素-7-O-β-D-葡萄糖苷的HPLC-UV分析方法，以葛根素为内标，色谱柱为Synergi C_(18)(250 mm×4.6 mm，I．D．4μm)，流动相为乙腈和0.5％冰醋酸水溶液梯度洗脱。4个成分的日内和日间精密度(RSD)均小于11.6％，准确度(RE)在±8.9％范围内，提取回收率不低于70.0％。又建立了大鼠血浆样品中4个化学成分分别测定的HPLC-UV分析方法，均符合生物样品分析方法指导原则的有关要求。用所建立的分析方法研究了槲寄生提取液静脉给药、4个单体混合液静脉给药、4个单体溶液分别静脉给药后大鼠体内的药动学行为。结果表明上述三种情况下各成分的给药剂量相同，但药动学行为受不同存在形式的影响具有较大差异。
本研究将中药化学、分析化学、生药学、药理学、药代动力学等手段相结合，研究了槲寄生的化学成分，建立了槲寄生药材的质量评价标准，探讨了相关活性成分的药代动力学过程，为中药现代化做了有意义的探索。
The branches with leaves of Viscum coloratum is a traditional Chinese medicine, named as Hujisheng in pharmacopoeia of PRC. The chemical constituents, quality control methods and the pharmacokinetics of Viscum coloratura were investigated in detail.
The chemical constituents of Viscum coloratum were systematically studied and 18 compounds were purified with silica gel, polyamide, sephadex LH-20 and ODS column chromatography. Utilizing chemical and spectroscopic methods (UV, NMR, MS), the structures of 15 compounds were fully characterized. One of these constituents was a novel compound: 1, 7-di- (4-hydroxybenzic)- heptane-1,4- diene-3- ketone; one of them was new nature product: 5-hydroxy- 3, 7, 3'- trimethoxyflavone -4'-O-β-D- glucoside; and one of these constituents was isolated from Viscum for the first time: 5, 7, 4'- trihydroxy-3, 3'-dimethoxyflavone.
The methods of HPLC and GC fingerprint analysis were established for the quality control of Viscum coloratum after investigating chromatographic and extracting condition. The samples from different origins and different hosts were analyzed with cluster analysis, and the data were used for similarity evaluation with angle cosine and correlation coefficient as measurement. There was significant difference between herb and their hosts while dependability of herb from different hosts or from different origins was high, which might be the results that effects of hosts on the fingerprints of herb were negligible. Dependability between HPLC fingerprints and GC fingerprints was small because information was different from different constituents. So these methods should be lay particular emphasis on according to clinical application during evaluating the quality of unknown samples.
The quality control methods of Viscum coloratum were studies. An HPLC-UV method was developed for the simultaneous quantification of those five constituents: syringin, homoeriodictyol -7-O-β-D- apiose (1→5)-β-D- apiose (1→2)-β-D- glucoside, homoeriodictyol -7-O-β-D- apiose (1→2)-β-D- glucoside, homoeriodictyol -7-O-β-D-glucoside and homoeriodictyol, in Viscum coloratum. The samples from different original area and different hosts were detected, with the results that there were evident differences from different origins and that content in the leaves were higher than that of branches. This method for analysis was simple and accurate, and was basics of quality control for Viscum coloratum. 22 essential oil of Viscum coloratum were identified with Gas Chromatography tandem Mass Spectrum comparing with standard substances, which supply the base for advanced research on essential oil of Viscum coloratum.
Homoeriodictyol -7-O-β-D- glucoside, possessing various pharmacological effects, was paid close attention to. A specific, reproducible, and accurate method was developed for the determination of homoeriodictyol =7-O-β-D- glucoside in rat plasma with vanillin as internal standard. The HPLC separation was achieved on a Diamonsil C_(18) (200 mm×4.6 mm, I.D. 5μm) column. The mobile phase consisted of methanol - 0.5 % glacial ethanol acid solution (45:55, v/v) with a flow rate of 1.0 ml/min. The UV detection wavelength was set at 280 nm. The extraction recoveries exceeded 70.0 %. Intra-day RSD and inter-day RSD were both less than 9.7 %. Accuracy (RE) ranged from -0.8 % to 5.4 %. This method was applied to the pharmacokinetic study of it in rat plasma with the parameters: Ke 0.73 h~(-1), t_(1/2) 1.56 h, AUC_(0～t) 7.16μg-h/ml, AUC_(0～∞) 7.82μg.h/ml. Homoeriodictyol -7-O-β-D- glucoside was found to be metabolized into aglycone, homoeriodictyol, in rat urine after i.v. administration. So another method with HPLC-MS was developed to study the distribution and excretion of homoeriodictyol -7=O-β-D-glucoside and its active metabolite homoeriodictyol. The HPLC separation was achieved on a Luna C_(18) (150mm×4.6mm, I.D. 5μm) column. The mobile phase was a methanol-water mixture (70:30, v/v) containing 0.1% of formic acid at a flow rate of 0.8 ml/min. Homoeriodictyol -7-O-β-D- glucoside showed a quick distribution into rat tissues with the dosage of intravenous injection of homoeriodictyol -7-O-β-D- glucoside. The contents of it in small intestine and liver were higher than others, and decrease with the prolongation of time in almost all tissues. Homoeriodictyol -7-O-β-D- glucoside was metabolized to homoeriodictyol which could be detected in most of tissues, and the content of kidney was the highest. After intravenous injection of homoeriodictyol -7-O-β-D-glucoside, 11.06 % of administration dosage as original glucoside and 5.73 % as aglycone were detected in urine.
An HPLC-UV method was developed for the simultaneous quantification of those four constituents: syringin, homoeriodictyol -7-O-β-D- apiose (1→5)-β-D- apiose (1→2)-β-D- glucoside, homoeriodictyol -7-O-β-D- apiose (1→2)-β-D- glucoside, homoeriodictyol -7-O-β-D- glucoside, in rat plasma with puerarin as internal standard. The HPLC separation was achieved on a Synergi C_(18) (250 mm×4.6 mm, I. D. 4μm, Phenonex) column. The mobile phase consisted of acetonitrile - 0.5 % glacial ethanol acid with gradient elution at a flow rate of 1.0 ml/min The UV detection wavelength was set at 280 nm. Intra-day RSD and inter-day RSD were both less than 11.6 % for these constituents. Accuracy ranged from -7.9 % to 5.6 % indicated with relative error (RE). The extraction recoveries exceeded 70.0 %. Another four HPLC-UV methods were developed to determine these four constituents respectively and all these methods were consistent with the guide for analysis of biological samples. They were applied to pharmacokinetic research after intravenous administration of monomers, mixed liquor of four monomers and Viscum coloratum extracts. The pharmacokinetic characteristics were significantly different because of the effects of co-existing compounds and different confirmation even with the same dosages.
Combining the utilization of phytochemistry, pharmaceutical analysis, pharmacognosy, pharmacology and pharmacokinetics, the constituents and quality assessment standards for Viscum coloratum were studied, and the metabolism of this medicinal herb and its active constituents were also investigated. This research provided a beneficial exploration for the modernization of traditional Chinese medcine.
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