大黄素-8-O-β-D-葡萄糖苷多晶型研究及其对药效学和药动学的影响
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摘要
大黄素-8-O-β-D-葡萄糖苷是从何首乌中提取的单体化合物。何首乌治疗老年性痴呆的疗效已在长期的医学实践中得到证实。因此，对大黄素-8-O-β-D-葡萄糖苷的药效学研究及进一步的药代动力学研究就显得十分必要。
随着新药研究的飞速发展，药物的多晶型现象越来越受到重视。特别是在药剂学的研究的过程中，由于药物的多晶型的存在，使得不同晶型的药物在理化性质、药效学、药物的吸收、分布及代谢等方面有所不同。研究由于药物的多晶型所造成的理化性质、药效学、药物的吸收、分布及代谢等方面的差异，是本文的主要目的。
本文采用不同溶剂重结晶的方法制备了大黄素-8-O-β-D-葡萄糖苷的两种不同的晶型，经过核磁共振、差热分析、红外吸收光谱、X-粉末衍射及HPLC法的研究，发现大黄素-8-O-β-D-葡萄糖苷存在至少两种的不同晶型，分别命名为α-PMEG及β-PMEG。同时，对两种晶型的药效学及药物代谢动力学的内容进行了初步的研究。
我们经过对两种晶型的大黄素-8-O-β-D-葡萄糖苷治疗由亚硝酸钠和东莨菪碱造成的小鼠学习记忆障碍模型，来观察大黄素-8-O-βD-葡萄糖苷(PMEG)对小鼠学习记忆的影响。结果发现，两种晶型的大黄素-8-O-β-D-葡萄糖苷均能显著提高正常及学习记忆功能障碍小鼠的学习记忆功能。急性毒性实验结果表明，MTD为4.0g／kg体重，此剂量为药效学有效剂量的200倍。据此，可以认为两种晶型的PMEG用于促智在有效剂量范围内无毒性。
PMEG经紫外全波长扫描发现，在267nm处有最大吸收，以此波长作为PMEG的检测波长，采用反相HPLC法检测其在大鼠体内的药物代谢动力学过程。结果发现，两种晶型的PMEG在大鼠体内的吸收过程表现为一级吸收，低、中、高剂量的α型PMEG(0.1mg／ml、0.2mg／ml、0.4mg／ml)的AUC值(梯形法计算)分别为1146.387±1221.110、3372.051±432.672、4708.859±400.365；β型PMEG(0.1mg／ml、0.2mg／ml、0.4mg／ml)的AUC值分别为2272.8174±140.703、3608.599±252.403、5237.279+280.800。两种晶型PMEG的对应浓度的AUC值没有显著性差异。
中文摘要 第二军医大学药学院 工怔
通过对两种晶型的PMEG体内分布的研究发现，在所检测的心、肝、脑。
肾等四个器官中分布较多，均在240min左右达到峰值，两种晶型之间没有显著
性差异。
对两种晶型的PMEG排泄物研究发现，大约有45％左右的原形药物经尿及
粪便排泄出体外。
本文对PMEG的肠吸收进行了研究，研究结果发现，在十二指肠、空肠。
回肠、结肠的吸收百分率分别为（14＊5L0．25）％、（12．45＊0．59）％、（11．37L0．77）％。
（6石6f0．85）％，总吸收率约为45％。
以上结果表明，大黄素．8－O－po－葡萄糖昔可以用做口服给药，以治疗老年
性痴呆症。可以进一步对其剂型进行研究。
Emodin-8-O- P -D-glucopyranoside ( PMEG ) is extracted from Polygonum multiflorum Thunb. The curative effect of Polygonum multiflorum Thunb on AD has been confirmed for a long time. It is very important to study on the pharmacodynamics and pharmcokinetics.
With the rapid development of the new drug research, more and more attention is being taken to the phenomenon of drug polymorphism. Particularly in the process of pharmaceutics study, as the result of polymorphism, different crystals of the same drug show the differences in physical and chemical characteristics, pharmcodynamics and pharmcokinetics, such as drug absorption, distribution and metabolism. The main aim of this thesis was to study these differences resulting from polymorphism of the new drug PMEG.
PMEG was recrystalized with different solvents and two different crystalforms were obtained, which were confirmed and characterized by HPLC, IR, NMR, DTA and X-ray powder diffractometry. We named them a-PMEG and P-PMEG respectively. The enteric absorption, distribution, metabolism and pharmacodynamics of the two crystalforms were studied.
PMEG shows the maximum absorption at 267nm by UV spectrophotometry scan. A HPLC method was established to determine the plasma concentration of PMEG. Pharmacokinetics study was carried out in mice which showed that the absorption process correlated the first order equation. The AUC of a-PMEG at low, medium and high dosage of 0.1,0.2,0.4mg/ml were 1146.39+1221.11,3372.051 + 432.67,4708.86 + 400.36 respectively, while the AUC of p-PMEG at the corresponding dose were 2272.82?40.70,3608.60?52.40,5237.28?80.80.There were no significantly difference between the AUC of the two crystals at the corresponding dosage.
In the study of the two crystal forms distribution in mice after oral administration PMEG, most of the two crystal forms were distributed into the four organs of the heart, liver, brain and kidney, reaching the maximum concentration at about 4h. There was no significant difference in the distribution of the two crystals.
We also found that there are about 50% original PMEG excreted in urine and dejecta.
In the study of the absorbance of PMEG in intestines of rats, we found that the absorbance in duodenum, jejunum, ileum, colon is (14.65?.25)%, (12.45?.59)% , (11.37?.77)% and (6.66?.85)% . The total absorbance of PMEG is about 45%.
Above all, PMEG can be used to treat AD, and it's preparations should be studied in the future.
随着新药研究的飞速发展，药物的多晶型现象越来越受到重视。特别是在药剂学的研究的过程中，由于药物的多晶型的存在，使得不同晶型的药物在理化性质、药效学、药物的吸收、分布及代谢等方面有所不同。研究由于药物的多晶型所造成的理化性质、药效学、药物的吸收、分布及代谢等方面的差异，是本文的主要目的。
本文采用不同溶剂重结晶的方法制备了大黄素-8-O-β-D-葡萄糖苷的两种不同的晶型，经过核磁共振、差热分析、红外吸收光谱、X-粉末衍射及HPLC法的研究，发现大黄素-8-O-β-D-葡萄糖苷存在至少两种的不同晶型，分别命名为α-PMEG及β-PMEG。同时，对两种晶型的药效学及药物代谢动力学的内容进行了初步的研究。
我们经过对两种晶型的大黄素-8-O-β-D-葡萄糖苷治疗由亚硝酸钠和东莨菪碱造成的小鼠学习记忆障碍模型，来观察大黄素-8-O-βD-葡萄糖苷(PMEG)对小鼠学习记忆的影响。结果发现，两种晶型的大黄素-8-O-β-D-葡萄糖苷均能显著提高正常及学习记忆功能障碍小鼠的学习记忆功能。急性毒性实验结果表明，MTD为4.0g／kg体重，此剂量为药效学有效剂量的200倍。据此，可以认为两种晶型的PMEG用于促智在有效剂量范围内无毒性。
PMEG经紫外全波长扫描发现，在267nm处有最大吸收，以此波长作为PMEG的检测波长，采用反相HPLC法检测其在大鼠体内的药物代谢动力学过程。结果发现，两种晶型的PMEG在大鼠体内的吸收过程表现为一级吸收，低、中、高剂量的α型PMEG(0.1mg／ml、0.2mg／ml、0.4mg／ml)的AUC值(梯形法计算)分别为1146.387±1221.110、3372.051±432.672、4708.859±400.365；β型PMEG(0.1mg／ml、0.2mg／ml、0.4mg／ml)的AUC值分别为2272.8174±140.703、3608.599±252.403、5237.279+280.800。两种晶型PMEG的对应浓度的AUC值没有显著性差异。
中文摘要 第二军医大学药学院 工怔
通过对两种晶型的PMEG体内分布的研究发现，在所检测的心、肝、脑。
肾等四个器官中分布较多，均在240min左右达到峰值，两种晶型之间没有显著
性差异。
对两种晶型的PMEG排泄物研究发现，大约有45％左右的原形药物经尿及
粪便排泄出体外。
本文对PMEG的肠吸收进行了研究，研究结果发现，在十二指肠、空肠。
回肠、结肠的吸收百分率分别为（14＊5L0．25）％、（12．45＊0．59）％、（11．37L0．77）％。
（6石6f0．85）％，总吸收率约为45％。
以上结果表明，大黄素．8－O－po－葡萄糖昔可以用做口服给药，以治疗老年
性痴呆症。可以进一步对其剂型进行研究。
Emodin-8-O- P -D-glucopyranoside ( PMEG ) is extracted from Polygonum multiflorum Thunb. The curative effect of Polygonum multiflorum Thunb on AD has been confirmed for a long time. It is very important to study on the pharmacodynamics and pharmcokinetics.
With the rapid development of the new drug research, more and more attention is being taken to the phenomenon of drug polymorphism. Particularly in the process of pharmaceutics study, as the result of polymorphism, different crystals of the same drug show the differences in physical and chemical characteristics, pharmcodynamics and pharmcokinetics, such as drug absorption, distribution and metabolism. The main aim of this thesis was to study these differences resulting from polymorphism of the new drug PMEG.
PMEG was recrystalized with different solvents and two different crystalforms were obtained, which were confirmed and characterized by HPLC, IR, NMR, DTA and X-ray powder diffractometry. We named them a-PMEG and P-PMEG respectively. The enteric absorption, distribution, metabolism and pharmacodynamics of the two crystalforms were studied.
PMEG shows the maximum absorption at 267nm by UV spectrophotometry scan. A HPLC method was established to determine the plasma concentration of PMEG. Pharmacokinetics study was carried out in mice which showed that the absorption process correlated the first order equation. The AUC of a-PMEG at low, medium and high dosage of 0.1,0.2,0.4mg/ml were 1146.39+1221.11,3372.051 + 432.67,4708.86 + 400.36 respectively, while the AUC of p-PMEG at the corresponding dose were 2272.82?40.70,3608.60?52.40,5237.28?80.80.There were no significantly difference between the AUC of the two crystals at the corresponding dosage.
In the study of the two crystal forms distribution in mice after oral administration PMEG, most of the two crystal forms were distributed into the four organs of the heart, liver, brain and kidney, reaching the maximum concentration at about 4h. There was no significant difference in the distribution of the two crystals.
We also found that there are about 50% original PMEG excreted in urine and dejecta.
In the study of the absorbance of PMEG in intestines of rats, we found that the absorbance in duodenum, jejunum, ileum, colon is (14.65?.25)%, (12.45?.59)% , (11.37?.77)% and (6.66?.85)% . The total absorbance of PMEG is about 45%.
Above all, PMEG can be used to treat AD, and it's preparations should be studied in the future.
引文
1.Brion JP. The Neurobiology of Alzheimer's Disease. ACTA Clin Belg 1996;51:80
2.Takeshi Uchida. Polymorphism of Tegafur: Physico-chemical Properties of Four Polymorphs. Cheme. Pharm. Bull 1993;41(9):1632-1635.
3.Yoshiaki Kawashima. Characterization of Polymorphs of Tranilast Anhydrate and Tranilast Monohydrate When Crystallizaed by Two Solvent Change Spherical Crystallization Techniques. Journal of Pharmaceutical Sciences. 1991;80(5):
4.Robert J. Behme. Heat of Fusion Measurement of a low Melting Polymorph of Carbamazepine That Undergoes Multiple-phase Changes During Differential Scanning Calorimetry Analysis. Journal of Pharmaceutical Sciences. 1991;80(10):
5．陈万生．何首乌活性及品质评价．第二军医大学博士论文．2000年．
2.Takeshi Uchida. Polymorphism of Tegafur: Physico-chemical Properties of Four Polymorphs. Cheme. Pharm. Bull 1993;41(9):1632-1635.
3.Yoshiaki Kawashima. Characterization of Polymorphs of Tranilast Anhydrate and Tranilast Monohydrate When Crystallizaed by Two Solvent Change Spherical Crystallization Techniques. Journal of Pharmaceutical Sciences. 1991;80(5):
4.Robert J. Behme. Heat of Fusion Measurement of a low Melting Polymorph of Carbamazepine That Undergoes Multiple-phase Changes During Differential Scanning Calorimetry Analysis. Journal of Pharmaceutical Sciences. 1991;80(10):
5．陈万生．何首乌活性及品质评价．第二军医大学博士论文．2000年．