水飞蓟宾卵磷脂复合物的生物药剂学研究
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摘要
本文的水飞蓟宾卵磷脂复合物的生物药剂学研究,从以下五方面获得了具有科学意义和应用价值的研究结果。
1.建立了用于制备水飞蓟宾A和水飞蓟宾B对照品的制备高效液相色谱法(pre-HPLC法),并建立了水飞蓟宾卵磷脂复合物(SPC)中水飞蓟宾A和B各自的高效液相测定法。此法简单,准确,可用于水飞蓟宾/素及其制剂中水飞蓟宾A和B的测定,为水飞蓟宾/素及其制剂更为严格的质量控制提供了技术保证。
2.分别建立了大鼠和人血浆中水飞蓟宾A和B测定的HPLC/MS/MS法,并用所建方法分别进行了SPC中水飞蓟宾A和B在大鼠和人体内的药代动力学研究。结果显示水飞蓟宾A和B在大鼠体内的绝对生物利用度分别为2.74%和1.82%;在大鼠实验的3个剂量组下,水飞蓟宾A和B均呈线性动力学特征;在大鼠实验中,药代动力学参数在水飞蓟宾A和B间均无显著性差异,但水飞蓟宾A和B在人体内有不同的药代动力学特征。
3.建立了大鼠组织匀浆中水飞蓟宾A和B测定的HPLC/MS/MS测定法,并对大鼠灌胃给予水飞蓟宾56mg/kg后,脑、心、肺、肝、脾、肾、胃、小肠、睾丸、子宫及卵巢各组织匀浆中水飞蓟宾A和B的浓度进行了测定。结果显示,在3个时间组(15min、1h和3h),胃,肠和肝中水飞蓟宾A和B的浓度均较高。
4.把水飞蓟宾作为一个整体,建立了人血浆中水飞蓟宾测定的HPLC-UV法,并用所建立的方法进行了SPC在人体内的药代动力学和相对生物利用度研究,结果显示在人体内水飞蓟宾呈线性动力学特征;SPC胶囊相对于水飞蓟素胶囊和水飞蓟宾葡甲胺片的生物利用度分别为270.4士139.6%和125.3±46.4%。
5.以小鼠和大鼠为实验动物,对SPC抗四氯化碳致急性肝损伤的保护作用进行了研究。结果显示SPC抗急性肝损伤的作用强于水飞蓟宾/素或其制剂,也强于卵磷脂;卵磷脂对水飞蓟宾的抗急性肝损伤具有协同作用,其不仅通过提高水飞蓟宾的生物利用度增强药效,而且其自身也具有保肝作用。
Through the biopharmaceutical studies of silybin– phosphatidylcholine complex (SPC), valuable results that are both academic and practical were achieved as follows:
1. A novel preparative HPLC method separating silybin was developed to meet the need for both silybin A and silybin B standard. After the preparation of silybin A and silybin B standard, a simple and accurate HPLC method was developed to determine silybin A and silybin B, respectively, which supplied a strong support for the accurate determination of silybin A and silybin B in silybin/silymarin or their preparations
2. A simple,sensitive, selective and reproducible liquid chromatography–tandem mass spectrometry(LC/MS/MS) method was developed for the quantification of silybin A and silybin B in rat and human plasma, and applied to the stereospecific analysis of silybin in plasma samples from pharmacokinetic studies in rat and human. The absolute bioavailability of silybin A and B in rat were 2.74% and 1.82%, respectively. The dose-independent pharmacokinetics was observed at three different administered doses to rat . In human, pharmacokinetic parameters between silybin A and B were different although those showed no significant difference between silybin A and B in rats.
3. A simple, sensitive, selective and reproducible LC/MS/MS method was developed for the quantification of silybin A and silybin B in different tissues of rat, such as brain, heart, lung, liver, spleen, kidney, stomach, intestine, testicle, uterus and ovary. It was found that the most concentrations of silybin A and B were detected in the stomach, intestine and liver at three different times (15min, 1h and 3h).
4. Taking silybin as a single entity, a new HPLC-UV method of determining silybin in human plasma was developed, and using the new developed method the pharmacokinetic of SPC was studied in healthy male Chinese volunteers. The dose-independent pharmacokinetics was observed after a single oral administration of SPC at three different doses. Through the study of relative bioavailability of SPC, it was showed that relative bioavailabilities of SPC were 270.4±139.6% and 125.3± 46.4% compared to silymarin and silybin meglumine, respectively.
5. The hepatoprotective potential of SPC was evaluated in rat and mice against CCl4-induced liver damage. Through the study, it was found that the hepatoprotective activity of SPC was better than silybin/silymarin or their preparations, and also phosphatidylcholine (PC). The hepatoprotective potential of SPC was improved not only by the improvement of bioavailability of silybin according to complex silybin with PC, also by the synergic action of PC.
1.建立了用于制备水飞蓟宾A和水飞蓟宾B对照品的制备高效液相色谱法(pre-HPLC法),并建立了水飞蓟宾卵磷脂复合物(SPC)中水飞蓟宾A和B各自的高效液相测定法。此法简单,准确,可用于水飞蓟宾/素及其制剂中水飞蓟宾A和B的测定,为水飞蓟宾/素及其制剂更为严格的质量控制提供了技术保证。
2.分别建立了大鼠和人血浆中水飞蓟宾A和B测定的HPLC/MS/MS法,并用所建方法分别进行了SPC中水飞蓟宾A和B在大鼠和人体内的药代动力学研究。结果显示水飞蓟宾A和B在大鼠体内的绝对生物利用度分别为2.74%和1.82%;在大鼠实验的3个剂量组下,水飞蓟宾A和B均呈线性动力学特征;在大鼠实验中,药代动力学参数在水飞蓟宾A和B间均无显著性差异,但水飞蓟宾A和B在人体内有不同的药代动力学特征。
3.建立了大鼠组织匀浆中水飞蓟宾A和B测定的HPLC/MS/MS测定法,并对大鼠灌胃给予水飞蓟宾56mg/kg后,脑、心、肺、肝、脾、肾、胃、小肠、睾丸、子宫及卵巢各组织匀浆中水飞蓟宾A和B的浓度进行了测定。结果显示,在3个时间组(15min、1h和3h),胃,肠和肝中水飞蓟宾A和B的浓度均较高。
4.把水飞蓟宾作为一个整体,建立了人血浆中水飞蓟宾测定的HPLC-UV法,并用所建立的方法进行了SPC在人体内的药代动力学和相对生物利用度研究,结果显示在人体内水飞蓟宾呈线性动力学特征;SPC胶囊相对于水飞蓟素胶囊和水飞蓟宾葡甲胺片的生物利用度分别为270.4士139.6%和125.3±46.4%。
5.以小鼠和大鼠为实验动物,对SPC抗四氯化碳致急性肝损伤的保护作用进行了研究。结果显示SPC抗急性肝损伤的作用强于水飞蓟宾/素或其制剂,也强于卵磷脂;卵磷脂对水飞蓟宾的抗急性肝损伤具有协同作用,其不仅通过提高水飞蓟宾的生物利用度增强药效,而且其自身也具有保肝作用。
Through the biopharmaceutical studies of silybin– phosphatidylcholine complex (SPC), valuable results that are both academic and practical were achieved as follows:
1. A novel preparative HPLC method separating silybin was developed to meet the need for both silybin A and silybin B standard. After the preparation of silybin A and silybin B standard, a simple and accurate HPLC method was developed to determine silybin A and silybin B, respectively, which supplied a strong support for the accurate determination of silybin A and silybin B in silybin/silymarin or their preparations
2. A simple,sensitive, selective and reproducible liquid chromatography–tandem mass spectrometry(LC/MS/MS) method was developed for the quantification of silybin A and silybin B in rat and human plasma, and applied to the stereospecific analysis of silybin in plasma samples from pharmacokinetic studies in rat and human. The absolute bioavailability of silybin A and B in rat were 2.74% and 1.82%, respectively. The dose-independent pharmacokinetics was observed at three different administered doses to rat . In human, pharmacokinetic parameters between silybin A and B were different although those showed no significant difference between silybin A and B in rats.
3. A simple, sensitive, selective and reproducible LC/MS/MS method was developed for the quantification of silybin A and silybin B in different tissues of rat, such as brain, heart, lung, liver, spleen, kidney, stomach, intestine, testicle, uterus and ovary. It was found that the most concentrations of silybin A and B were detected in the stomach, intestine and liver at three different times (15min, 1h and 3h).
4. Taking silybin as a single entity, a new HPLC-UV method of determining silybin in human plasma was developed, and using the new developed method the pharmacokinetic of SPC was studied in healthy male Chinese volunteers. The dose-independent pharmacokinetics was observed after a single oral administration of SPC at three different doses. Through the study of relative bioavailability of SPC, it was showed that relative bioavailabilities of SPC were 270.4±139.6% and 125.3± 46.4% compared to silymarin and silybin meglumine, respectively.
5. The hepatoprotective potential of SPC was evaluated in rat and mice against CCl4-induced liver damage. Through the study, it was found that the hepatoprotective activity of SPC was better than silybin/silymarin or their preparations, and also phosphatidylcholine (PC). The hepatoprotective potential of SPC was improved not only by the improvement of bioavailability of silybin according to complex silybin with PC, also by the synergic action of PC.
引文
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