普通针毛蕨总黄酮抗肿瘤作用及其药代动力学初步研究
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摘要
普通针毛蕨Macrothelypteris torresiana (Gaud.) Ching广泛分布于长江流域以南各省,资源十分丰富。本实验室前期研究发现由该植物提取制备的总黄酮类成分部位具有良好的抗肿瘤作用,其中主要化合物原芹菜素的含量占总黄酮提取物的重量百分比达45%以上。为了进一步探讨普通针毛蕨总黄酮抗肿瘤作用及其成药性,本课题围绕普通针毛蕨总黄酮有效部位进行了普通针毛蕨药材及其总黄酮提取物的质量评价研究；探讨了普通针毛蕨总黄酮提取物羟丙基伊环糊精包合工艺；对普通针毛蕨总黄酮包合剂与CMC-Na混悬剂平行对比进行了急性毒性、亚急性毒性、体内抗肿瘤及药代动力学等一系列探索性研究。
参照《中国药典》2005年版一部附录ⅨK所载灰分测定法、ⅨH所载水分测定法对10批干燥至恒重的普通针毛蕨细粉的总灰分、酸不溶性灰分及水分进行测定。以前期化学研究获得该药材的标志成分原芹菜素为对照,参照《中国药典》2005年版一部附录VA所载紫外-可见分光光度法检测样品中总黄酮的含量,HPLC法测定样品总提取物中原芹菜素含量,结果显示：生药材中总灰分不得超过8.31%,酸不溶性灰分不得超过3.90%,水分不得超过15.01%,t检验显示,上述指标,因产地不同,无显著性差异(p>0.05)；生药材中总黄酮成分不得低于3.31%,原芹菜素的含量不得低于0.84%；黄酮总提取物中原芹菜素含量不得低于37.06%。t检验显示,普通针毛蕨生药材中,因产地不同,总黄酮及原芹菜素含量有一定的差异(0.01 应用经典药理学研究方法对普通针毛蕨总黄酮提取物混悬剂与包合剂进行了急性毒性评价实验,按体重最高剂量6.67、2.14 g kg-1、以0.75组间距为稀释等级系数,共设8个剂量组,一次性小鼠灌胃给药,观察7天,Bliss法计算结果得出其LDso分别为2.7555、0.8707 g kg-1；亚急性毒性混悬剂按600、60、6 mgkg-1,包合剂按400、40、4mg kg-1体重给药,每日一次,连续灌胃给药14天,结果所有样品组的脏器系数、尿素氮、转氨酶与阴性对照组比较无显著性差异(p>0.05),但脏器HE染色切片结果显示高剂量组有轻微肝细胞颗粒变性,其它脏器未见损伤,两种剂型间无显著性差异。
体内抗肿瘤试验采用移植肿瘤S180荷瘤小鼠,以普通针毛蕨总黄酮水溶液和混悬剂均按体重60、30、15 mg k-1灌胃给药、包合剂按体重40、20、10 mgkg-1灌胃给药,阳性对照组均为五氟尿嘧啶20 mgkg-1、阴性对照组均为生理盐水等容量给药。每日2次,连用10天,结果显示水溶液抑瘤率较低(<33.14),而混悬剂(35.23-56.35%)、包合剂(25.45-54.57%)抑瘤率明显提高；后两者在本组内高、中剂量组间比较无显著性差异(p>0.05),低剂量组与高、中剂量组间有显著性差异(p<0.05)。与阳性对照组比较,包合剂和混悬剂的高、中剂量组无显著性差异(p>0.05),水溶液各剂量组有显著性差异(p<0.05)。
药代动力学研究以普通针毛蕨总黄酮混悬剂与包合物二种剂型均按体重100、200、300 mg kg-1,大鼠灌胃给药。采用Das 2.0、二室模型(two compartment model)和统计矩法(noncompartment model)进行分析,两者在大鼠体内均表现出明显的线性动力学特征,AUC与剂量成正比、消除半衰期与剂量无关,动力学过程基本一致。但是包合物延长了半衰期、缩短了达峰时间,峰浓度有所提高。总黄酮中原芹菜素在肝、肾、肺、脾、心等血流充沛的器官中分布较多,乳房、卵巢、子宫组织中有一定分布,脑、肌肉、脂肪分布较少。胆汁、尿液、粪便均有原芹菜素原型物排泄,且尿液>粪便>胆汁。包合物的粪便排泄量明显减少,说明胃肠吸收明显提高。血液、脏器组织中普遍存在一个新的代谢产物,由何而来?为何物?尚待进一步深入研究。
应用平衡透析法进行了普通针毛蕨主要黄酮化合物原芹菜素的血浆蛋白结合率研究,结果显示原芹菜素人血药透析袋内外平衡时间约为10 h,在低、中、高(200、500、1000μg L-1)浓度下,其血浆蛋白结合率为90.5±1.2%、89.6±1.7%、91.4±1.4%；鼠血药透析袋内外平衡时间约为6 h,在低、中、高(200、500、1000μg L-1)浓度下,鼠血浆蛋白结合率为80.7±2.2%、81.1±1.8%、81.9±1.3%。t检验说明原芹菜素在人、鼠血浆蛋白结合率之间有显著差异(p<0.01),但同一样品低、中、高浓度之间,蛋白结合率无显著性差异(p>0.05)。说明原芹菜素的人、鼠血浆蛋白结合率较高。
Macrothelypteris torresiana (Gaud.) Ching, which belongs to Thelypteridaceae family, is widely distributed in the south of China and has been used as folk medicine mainly for the treatment of diseases such as hydropsy and traumatic bleeding. In previous work, we have found that the total flavonoid fraction shows significant antitumor potential. In the total flavonoid fraction, the percentage of the protoapigenone, which is the main component, reaches up to 45%. In order to further investigate the antitumor activities of the total flavonoid fraction and obtain more data to explore it as a natural antitumor agent, The present study had the following objectives:(a) to establish the quality standard of Macrothelypteris torresiana and the total flavonoid fraction; (b) to optimize the inclusion process of the total flavonoid fraction by hydroxypropyl-β-cyclodextrin; (c) to compare and evaluate the acute and subacute toxicities, in vivo antitumor activities and pharmacokinetics of the total flavonoid fraction dissolved using sodium carboxymethyl cellulose (CMC-Na) and included by hydroxypropyl-β-cyclodextrin, respectively.
The contents of water, ashes, acid insoluble ashes of powdered material of Macrothelypteris torresiana were determined according to the standard methods recorded in Pharmacopoeia of the People's Republic of China (AppendixⅨK and IX H in Part one of the 2005 version). We treated the protoapigenone as the reference substance and used the Ultraviolet-visible spectrophotometry method (Appendix VA in Part one of the 2005 version) to determine the contents of total flavonoids in powdered material of Macrothelypteris torresiana. Also, a HPLC method was used to determine the content of protoapigenone. As a result, the limits of the content of water, ashes, and acid insoluble ashes in the powdered material of Macrothelypteris torresiana were 15.01%,8.31% and 3.90%. By the statistical analysis on the above data with a Student's t-test, there was no difference among different places of origin (p>0.05). In the powdered material of Macrothelypteris torresiana, the contents of total flavonoids were equal to or higher than 3.31%, and the minimum content of protoapigenone was not less than 0.84%; the minimum content of protoapigenone in total flavonoids extrcts was not less than 37.06% Additionally, by the statistical analysis on the content of protoapigenone with a Student's t-test, there were some difference among different places of origin (0.01 This study also used classical pharmacological methods to investigate the acute toxicities of the total flavonoid fraction dissolved using CMC-Na (preparation 1) and included by hydroxypropyl-β-cyclodextrin (preparation 2), respectively. Each preparation at different doses (the doses of preparations 1 and 2 were 6.67,5.00,3.75, 2.81,2.11,1.58,1.19,0.89 g kg-1 body wt. and 2.14,1.57,1.18,0.89,0.67,0.50, 0.37,0.28 g kg-1 body wt., respectively) were administered orally once. After administration, all externalmorphological, behavioral, neurologic, autonomic changes, number of dead and time to death, as well as some other toxic effects were recorded continuously at 1 day intervals over a period of 7 days. The Bliss method was used to obtain that LD50 were 2.7555,0.8707 g kg-1, respectively. Taking 0.5% CMC-Na and hydroxypropyl-β-cyclodextrin as negative controls, respectively, the subacute toxicities were performed. Multiple doses (600,60,6 mg kg-1 body wt. of preparation 1 and 400,40,4 mg kg-1 body wt. of preparation 2, respectively) were administered orally each day over a period of 14 days. As a result, there was no difference between the organ weights, urea nitrogen, and transaminase between treated groups and negative control groups (p>0.05). But, the HE staining results showed that there was granular degeneration of liver cells only in the high dose group, additionally, preparation 1 and 2 showed the same results.
The vivo antitumor investigation was performed on mouse sarcoma S-180 cells treated mice. The aqueous solution and suspension using CMC-Na of the total flavonoid fraction were administered orally at high, medium, low doses of 60,30, and 15 mg kg-1 body wt./day; inclusion of the total flavonoid fraction by hydroxypropyl-β-cyclodextrin at the doses of 40,20, and 10 mg kg-1 body wt./day; the standard drug 5-fluorouracil (20 mg kg-1 body wt./day) was administered orally to the positive control group. Sterile saline was administered orally in the same volume to the negative control group. The administration lasted for 10 days. The results showed that the inhibition ratios of tumor growth in suspension (35.23-56.35%) and inclusion (25.45-54.57%) groups were high than that of the aqueous solution group (<33.14%). the inhibition ratios of tumor growth in high and medium dose groups of both suspension and inclusion were almost the same (p>0.05), but the low dose group did not show enough high activities (p<0.05). Compared with positive control, there is no difference of the high and medium doses of both suspension and inclusion (p>0.05), but significant differences of all doses of the aqueous solution (p<0.05).
In this part, the pharmacokinetics of the suspension using CMC-Na and inclusion by hydroxypropyl-β-cyclodextrin of the total flavonoid fraction was performed. Doses (100,200,300 mg kg-1) of the suspension and inclusion were administered orally to rats, the two compartment model and noncompartment model were used to analyze protoapigenone in plasma by Das 2.0. We found that the two models both showed a significant linear kinetics in rats, and the AUC was proportional to the dose. Additionally, besides the half-life time had nothing to do with the dose, the two models had the same kinetics process. Anymore, the inclusion extended the half-life time, shortened peak time, and increased peak concentration. After administion, the protoapigenone from the total flavonoid fraction was mainly distributed in liver, kidney, lung, spleen and heart, which are organs with abundant blood flow, and some even distributed in breast, ovarian and uterine issues, but less distributed in brain, muscle and fat issues. In bile, urine and feces, we found certain amount of protoapigenone excreted as prototype, and compared the amount excreted, urine> feces> bile. After inclusion by hydroxypropyl-β-cyclodextrin, the excretion of the protoapigenone in feces was significantly reduced, thus the inclusion might promote the gastrointestinal absorption of protoapigenone. In all plasma and organs, there is a common metabolite, which might be formed from the degradation of protoapigenone, but it requires further in-depth study
The equilibrium dialysis combined with HPLC was carried out for the determination of the plasma protein binding rate of protoapigenone. From the results, we found that the balance time of dialysis was 10 h in human plasma, and the plasma protein binding rates of protoapigenone at low, middle and high concentrations (200、500、1000μg L-1) were 90.5±1.2%,89.6±1.7% and 91.4±1.4%, respectively. But the balance time of dialysis was 6 h in rat plasma, and the plasma protein binding rates of protoapigenone at low, middle and high concentrations were 80.7±2.2%,81.1±1.8% and 81.9±1.3%, respectively. Thus, the plasma protein binding rates of protoapigenone in both human and rat plasma were high enough. Additionally, there are significant differences between the plasma protein binding rates of protoapigenone in human and rat plasma (p<0.01), but no difference in low, middle or high concentrations (p>0.05).
参照《中国药典》2005年版一部附录ⅨK所载灰分测定法、ⅨH所载水分测定法对10批干燥至恒重的普通针毛蕨细粉的总灰分、酸不溶性灰分及水分进行测定。以前期化学研究获得该药材的标志成分原芹菜素为对照,参照《中国药典》2005年版一部附录VA所载紫外-可见分光光度法检测样品中总黄酮的含量,HPLC法测定样品总提取物中原芹菜素含量,结果显示：生药材中总灰分不得超过8.31%,酸不溶性灰分不得超过3.90%,水分不得超过15.01%,t检验显示,上述指标,因产地不同,无显著性差异(p>0.05)；生药材中总黄酮成分不得低于3.31%,原芹菜素的含量不得低于0.84%；黄酮总提取物中原芹菜素含量不得低于37.06%。t检验显示,普通针毛蕨生药材中,因产地不同,总黄酮及原芹菜素含量有一定的差异(0.01
体内抗肿瘤试验采用移植肿瘤S180荷瘤小鼠,以普通针毛蕨总黄酮水溶液和混悬剂均按体重60、30、15 mg k-1灌胃给药、包合剂按体重40、20、10 mgkg-1灌胃给药,阳性对照组均为五氟尿嘧啶20 mgkg-1、阴性对照组均为生理盐水等容量给药。每日2次,连用10天,结果显示水溶液抑瘤率较低(<33.14),而混悬剂(35.23-56.35%)、包合剂(25.45-54.57%)抑瘤率明显提高；后两者在本组内高、中剂量组间比较无显著性差异(p>0.05),低剂量组与高、中剂量组间有显著性差异(p<0.05)。与阳性对照组比较,包合剂和混悬剂的高、中剂量组无显著性差异(p>0.05),水溶液各剂量组有显著性差异(p<0.05)。
药代动力学研究以普通针毛蕨总黄酮混悬剂与包合物二种剂型均按体重100、200、300 mg kg-1,大鼠灌胃给药。采用Das 2.0、二室模型(two compartment model)和统计矩法(noncompartment model)进行分析,两者在大鼠体内均表现出明显的线性动力学特征,AUC与剂量成正比、消除半衰期与剂量无关,动力学过程基本一致。但是包合物延长了半衰期、缩短了达峰时间,峰浓度有所提高。总黄酮中原芹菜素在肝、肾、肺、脾、心等血流充沛的器官中分布较多,乳房、卵巢、子宫组织中有一定分布,脑、肌肉、脂肪分布较少。胆汁、尿液、粪便均有原芹菜素原型物排泄,且尿液>粪便>胆汁。包合物的粪便排泄量明显减少,说明胃肠吸收明显提高。血液、脏器组织中普遍存在一个新的代谢产物,由何而来?为何物?尚待进一步深入研究。
应用平衡透析法进行了普通针毛蕨主要黄酮化合物原芹菜素的血浆蛋白结合率研究,结果显示原芹菜素人血药透析袋内外平衡时间约为10 h,在低、中、高(200、500、1000μg L-1)浓度下,其血浆蛋白结合率为90.5±1.2%、89.6±1.7%、91.4±1.4%；鼠血药透析袋内外平衡时间约为6 h,在低、中、高(200、500、1000μg L-1)浓度下,鼠血浆蛋白结合率为80.7±2.2%、81.1±1.8%、81.9±1.3%。t检验说明原芹菜素在人、鼠血浆蛋白结合率之间有显著差异(p<0.01),但同一样品低、中、高浓度之间,蛋白结合率无显著性差异(p>0.05)。说明原芹菜素的人、鼠血浆蛋白结合率较高。
Macrothelypteris torresiana (Gaud.) Ching, which belongs to Thelypteridaceae family, is widely distributed in the south of China and has been used as folk medicine mainly for the treatment of diseases such as hydropsy and traumatic bleeding. In previous work, we have found that the total flavonoid fraction shows significant antitumor potential. In the total flavonoid fraction, the percentage of the protoapigenone, which is the main component, reaches up to 45%. In order to further investigate the antitumor activities of the total flavonoid fraction and obtain more data to explore it as a natural antitumor agent, The present study had the following objectives:(a) to establish the quality standard of Macrothelypteris torresiana and the total flavonoid fraction; (b) to optimize the inclusion process of the total flavonoid fraction by hydroxypropyl-β-cyclodextrin; (c) to compare and evaluate the acute and subacute toxicities, in vivo antitumor activities and pharmacokinetics of the total flavonoid fraction dissolved using sodium carboxymethyl cellulose (CMC-Na) and included by hydroxypropyl-β-cyclodextrin, respectively.
The contents of water, ashes, acid insoluble ashes of powdered material of Macrothelypteris torresiana were determined according to the standard methods recorded in Pharmacopoeia of the People's Republic of China (AppendixⅨK and IX H in Part one of the 2005 version). We treated the protoapigenone as the reference substance and used the Ultraviolet-visible spectrophotometry method (Appendix VA in Part one of the 2005 version) to determine the contents of total flavonoids in powdered material of Macrothelypteris torresiana. Also, a HPLC method was used to determine the content of protoapigenone. As a result, the limits of the content of water, ashes, and acid insoluble ashes in the powdered material of Macrothelypteris torresiana were 15.01%,8.31% and 3.90%. By the statistical analysis on the above data with a Student's t-test, there was no difference among different places of origin (p>0.05). In the powdered material of Macrothelypteris torresiana, the contents of total flavonoids were equal to or higher than 3.31%, and the minimum content of protoapigenone was not less than 0.84%; the minimum content of protoapigenone in total flavonoids extrcts was not less than 37.06% Additionally, by the statistical analysis on the content of protoapigenone with a Student's t-test, there were some difference among different places of origin (0.01
The vivo antitumor investigation was performed on mouse sarcoma S-180 cells treated mice. The aqueous solution and suspension using CMC-Na of the total flavonoid fraction were administered orally at high, medium, low doses of 60,30, and 15 mg kg-1 body wt./day; inclusion of the total flavonoid fraction by hydroxypropyl-β-cyclodextrin at the doses of 40,20, and 10 mg kg-1 body wt./day; the standard drug 5-fluorouracil (20 mg kg-1 body wt./day) was administered orally to the positive control group. Sterile saline was administered orally in the same volume to the negative control group. The administration lasted for 10 days. The results showed that the inhibition ratios of tumor growth in suspension (35.23-56.35%) and inclusion (25.45-54.57%) groups were high than that of the aqueous solution group (<33.14%). the inhibition ratios of tumor growth in high and medium dose groups of both suspension and inclusion were almost the same (p>0.05), but the low dose group did not show enough high activities (p<0.05). Compared with positive control, there is no difference of the high and medium doses of both suspension and inclusion (p>0.05), but significant differences of all doses of the aqueous solution (p<0.05).
In this part, the pharmacokinetics of the suspension using CMC-Na and inclusion by hydroxypropyl-β-cyclodextrin of the total flavonoid fraction was performed. Doses (100,200,300 mg kg-1) of the suspension and inclusion were administered orally to rats, the two compartment model and noncompartment model were used to analyze protoapigenone in plasma by Das 2.0. We found that the two models both showed a significant linear kinetics in rats, and the AUC was proportional to the dose. Additionally, besides the half-life time had nothing to do with the dose, the two models had the same kinetics process. Anymore, the inclusion extended the half-life time, shortened peak time, and increased peak concentration. After administion, the protoapigenone from the total flavonoid fraction was mainly distributed in liver, kidney, lung, spleen and heart, which are organs with abundant blood flow, and some even distributed in breast, ovarian and uterine issues, but less distributed in brain, muscle and fat issues. In bile, urine and feces, we found certain amount of protoapigenone excreted as prototype, and compared the amount excreted, urine> feces> bile. After inclusion by hydroxypropyl-β-cyclodextrin, the excretion of the protoapigenone in feces was significantly reduced, thus the inclusion might promote the gastrointestinal absorption of protoapigenone. In all plasma and organs, there is a common metabolite, which might be formed from the degradation of protoapigenone, but it requires further in-depth study
The equilibrium dialysis combined with HPLC was carried out for the determination of the plasma protein binding rate of protoapigenone. From the results, we found that the balance time of dialysis was 10 h in human plasma, and the plasma protein binding rates of protoapigenone at low, middle and high concentrations (200、500、1000μg L-1) were 90.5±1.2%,89.6±1.7% and 91.4±1.4%, respectively. But the balance time of dialysis was 6 h in rat plasma, and the plasma protein binding rates of protoapigenone at low, middle and high concentrations were 80.7±2.2%,81.1±1.8% and 81.9±1.3%, respectively. Thus, the plasma protein binding rates of protoapigenone in both human and rat plasma were high enough. Additionally, there are significant differences between the plasma protein binding rates of protoapigenone in human and rat plasma (p<0.01), but no difference in low, middle or high concentrations (p>0.05).
引文
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