人参皂苷元的药代动力学研究
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摘要
人参皂苷主要有原人参二醇(Protopanaxadiol, PPD)型、原人参三醇(Protopanaxatriol, PPT)型、齐墩果酸(Oleanic Acid, OA)型三种类型,其具有广泛的生物学活性,包括免疫调节、抗肿瘤、提高学习记忆、抗衰老、抗炎、抗痴呆、抗疲劳和促进造血等。但是人参皂苷本身不易被吸收,生物利用度较低。大量研究表明,人参皂苷在胃肠道去糖代谢后形成苷元或次苷,这些成分更容易被胃肠道吸收,且活性较皂苷增强。人参皂苷元混合物DS-1226系采用专有技术从人参茎叶中提取、水解、精制而成的一种类似人参皂苷肠代谢组合物的新型中药有效组份,该产品及技术已获得中国、美国、加拿大、欧盟、台湾等8个国家或地区的授权专利,其主要成分为PPT(33%)和PPD(16%)。行为学实验表明DS-1226对睡眠干扰所致的学习记忆障碍具有改善作用,此外其还对化疗所致的骨髓抑制有保护作用。本研究通过液相色谱-质谱联用(LC-MS)技术,以整体动物研究给予DS-1226后其主要成分PPT和PPD的药代动力学特性,并利用Caco-2细胞模型、体外血脑屏障模型对PPD和PPT单体的肠吸收机制和透血脑屏障能力进行研究,同时,对DS-1226潜在的药物相互作用风险进行了探讨。
1、本文首先建立了同时测定生物样品(血浆、皮层和海马)中PPT和PPD的高效,灵敏,稳定可靠的LC-MS分析方法。本方法以齐墩果酸作为内标,采用二氯甲烷液液萃取方法处理生物样品,在流动相中加入0.05mmol/L氯化铵以提高检测灵敏度,采用加氯母离子m/z511.6(PPT), m/z495.9(PPD), m/z455.5(OA,内标)作为检测离子。结果显示,血浆样品和海马匀浆液中PPT和PPD的最低检测限均为10.0ng/mL,最低定量限均为20.0ng/mL。皮层匀浆液中PPT和PPD的最低检测限为3.3ng/mL,最低定量限为6.7ng/mL。对日内、日间精密度和准确度进行了考察,结果表明此方法的精密度和准确度均符合生物样品分析的要求。
2、应用新建立的LC-MS分析方法,对静脉(30mg/kg)、口服(75mg/kg)和肝门静脉(75mg/kg)等不同途径给予DS—1226后其主要成分PPT和PPD在大鼠体内的药代动力学特性进行研究,同时对PPT和PPD的胃肠道稳定性进行研究。体内药代动力学实验结果表明,口服给药后PPT和PPD的tmax,t1/2分别为0.58h,0.95h和1.82h,3.76h,表明PPT的达峰时间和体内消除速度相对于PPD均较快。PPT的口服生物利用度很低,仅为3.69%,而PPD具有较好的生物利用度,为48.12%。肝门给药时PPT和PPD的生物利用度分别为101.27%和100.54%,表明不存在肝首过效应,说明肝首过效应不是导致PPT生物利用度低的原因。静脉给药后PPT和PPD可进入脑组织,且在海马中含量较皮层中高。胃肠道稳定性研究结果显示,PPT在pH1.2缓冲液、胃内容物中发生明显的降解,推测其在胃中不稳定性可能是导致其生物利用度低的原因之一。
3、本文在建立体外Caco-2细胞摄取、转运模型的基础上,对PPT和PPD的肠吸收机理进行了研究。结果表明,PPT和PPD在不同浓度(10,20,40μM)下表观渗透系数(Papp AP→BL)分别为(12.40～15.35)×10-6cm/s和(22.71～25.80)×10一cm/s,均属于吸收良好的药物。从AP→BL及BL→AP的转运量随浓度的增高而相应增大,而Papp值基本保持不变,外排比率均小于1.5。加入100μM维拉帕米后,PPT和PPD的Papp AP→BL与不加抑制剂组相比均无显著性差异,表明PPT和PPD在肠道上的转运方式均为被动扩散。
4、本文采用分离、纯化得到的原代大鼠脑微血管内皮细胞和星形胶质细胞通过共培养方式建立体外血脑屏障模型,然后对PPT、PPD的透血脑屏障能力进行考察。实验结果显示,PPT和PPD在不同浓度(10,20,40μM)下表观渗透系数(Papp AP→BL)分别为(30.30～34.39)×10-6cm/s和(4.09～5.08)×10-6cm/s。PPT的Papp值比PPD高约8倍,表明PPT相对于PPD更容易透过血脑屏障。
5、最后,本文采用Cocktail探针底物法和Rho-123摄取法分别评价DS-1226对肝微粒体CYP450酶和P-糖蛋白(P-glycoprotein, P-gP)活性的影响。结果显示DS-1226对CYP3A4介导的睾酮6p-羟基化反应抑制最强,IC50为7.58μg/mL。对CYP2C19介导的奥美拉唑5-羟基化和CYP2C9介导的甲苯磺丁脲4。羟基化也有较强的抑制作用,IC50分别为13.28μg/mL和9.69μg/mL。对CYP2E1介导的氯挫沙宗6-羟基化和CYP2D6介导的右美沙芬O-脱烷基化则几乎无抑制作用,IC50分别为99.48μg/mL和114.90μg/mL。提示DS-1226有可能在体内通过抑制肝脏CYP酶而引起显著的药物相互作用。同时DS-1226对P-gp的有一定的抑制作用,但与阴性对照组无显著性差异(P>0.05)。
总之,本文通过静脉、口服、肝门静脉等不同给药途径给予DS-1226后研究PPT和PPD的体内药代动力学特性,并对影响其生物利用度的因素进行了探讨；同时,分别采用Caco-2细胞模型和体外血脑屏障模型对PPT和PPD单体的肠吸收机制和透血脑屏障能力进行了研究；最后,对DS-1226潜在的药物相互作用进行了初步研究。PPT仅比PPD在C-6多了一个羟基,但是二者的药动学特性表现出很大差异,PPD无论在血液循环系统还是脑组织中均具有较高的利用率。本研究为人参皂苷元类化合物的进一步研究和开发利用提供了思路,以便后续更深入的探讨其作用机制以及对其成药性做出评价。
Based on their chemical structures, ginsenosides are divided into three groups:protopanaxatriol (PPT), protopanaxadiol (PPD) and oleanane types. Ginsenosides had been found a wide range of biological activities, including immunomodulatory, anti-tumor, learning and memory improving, anti-aging, antiinflammatory, antidementia, antifatigue, hemopoietic function promotion and so on. However, ginsenosides themselves can not easily be absorbed and their bioavailabilities were poor. Many studies demonstrated that ginsenosides can be hydrolyzed in the gastrointestinal (GI) tract to form their metabolites including PPT and PPD, which are more easily absorbed into the body and displayed more potent activities than ginsenosides. Dammarane Sapogenins (DS-1226), which was prepared by proprietary technology to alkaline hydrolysis of total ginsenosides derived from the stem and leaf of Panax ginseng. This production and technology has already won patent rights at eight countries or regions, including China, USA, Canada, European Union, Taiwan, etc. DS-1226was mainly composed of33%PPT and16%PPD, and had been found with significant activities in improving learning and memory on cognitive dysfunction caused by sleep interruption in mice, and also decreasing chemotherapy-induced myelosuppression. In present study, we investigated the pharmacokinetic properties of PPT and PPD in rat plasma and brain using a LC-MS method when DS-1226was administrated to rats. The permeability through the small intestine and the blood-brain-barrier (BBB) were studied by using the Caco-2cell model and in vitro blood-brain barrier model, respectively. Finally, potentially drug-drug interaction of DS-1226was investigated.
1. A sensitive LC-MS method was developed for the simultaneous determination of PPT and PPD in rat plasma and brain tissue. The analytes were extracted with dichloromethane and using OA as an internal standard. In order to achieve the abundant and stable signals,0.05mmol/L ammonium chloride was added to the mobile phase, and the chloride adducted molecule ions [M+C1]-at m/z511.6,495.9and455.5were used for monitoring PPT, PPD and OA, respectively. The results indicated that the limits of detection and quantification for both PPT and PPD in rat plasma and hippocampal were10.0,20.0ng/ml, respectively. And both the limits of detection, quantification for PPT and PPD in rat cortex were3.3ng/ml,6.7ng/ml, respectively. The intra-day and inter-day precisions and the accuracies were satisfactory and indicated that the LC-MS method was suitable for biological analysis.
2. The pharmacokinetics of PPT and PPD in rats were studied after intravenously (i.v.,30mg/kg), oral (75mg/kg) and portal vein (p.v.,75mg/kg) administration of DS-1226. Their in vitro stabilities in the gastrointestinal (GI) tract were also investigated. The results showed that PPT was rapid absorption and eliminated rapidly from the body with averagetmax value of0.58h and t1/2,λz of0.95h after oral administration, while PPD was absorption and eliminated relatively slowly with tmax value of1.82h and t1/2,λz of3.76h. The absolute bioavailabilities of PPT and PPD were estimated as3.69%and48.12%, respectively.DS-1226was administrated to rats through the hepatic portal vein for exploring the hepatic first-pass effect of PPT and PPD. The results showed that the bioavailabilities of PPT and PPD were101.27%and100.54%, which indicated that hepatic first-pass should not be the reason for its low bioavailabilitiy. Both PPT and PPD could be detected in brain after i.v. administration, and their concentrations in hippocampal were relatively higher than that in cortex. The stability test found that PPT was instable both in pH1.2buffer and in the stomach content solution, indicated that the instability in the stomach might be one of the reasons for PPT poor bioavailabilitiy.
3. Their intestinal transport absorption were investigated by using the Caco-2cell monolayer model. The results showed that PPT and PPD at three concentrations (10,20and40μM) have good absorption transport with Papp AP→BL value of (12.40～15.35)×10-6cm/s and (22.71～25.80)×10-6cm/s. The transported amounts of PPT and PPD were all increased with the increase of loading concentrations, with no changes for Papp values, the ratios of Papp BL→AB/Papp AB→BL for PPD and PPT were less than1.5. Furthermore, the Papp values for PPD and PPT were determined in the presence of100μM verapamil, and were found similar with that of absence of verapamil. This suggests that passive diffusion is the main transport mechanism of both PPD and PPT.
4. In vitro BBB model by co-culture primary cultured brain endothelial cells and astrocytes was established, and permeability of PPT and PPD through BBB were investigated. The results showed that PPT and PPD at three concentrations (10,20and40μM) both could penetrate the BBB, and with PappAP→BL value of (30.30～34.39)×10-6cm/s and (4.09～5.08)×10-6cm/s. The Papp values for PPT was about eight times higher than that for PPD, which indicated that PPT could be penetrate the BBB more easily.
5. Finally, the inhibitory effect of DS-1226on the activities of hepatic microsomal CYP450enzymes were investigated by cocktail probe drugs, and the effect of DS-1226on the activity of P-gp was investigated by uptake of Rho-123. The results showed that DS-1226have significant inhibiting effects on the activity of CYP3A4, CYP2C9and CYP2C19, with the IC50value of7.58,9.69and13.28μg/mL, while the inhibiting effects on the activity of CYP2E1and CYP2D6were relatively weakly, with the IC50value of99.48μM and114.90μM. The results indicate that DS-1226might cause significant drug interactions by inhibiting hepatic CYP450enzymes in vivo. DS-1226has weak inhibition on P-gp, but there was no significant difference between DS-1226groups and negative control group (P>0.05).
In conclusion, the pharmacokinetic properties of PPT and PPD after i.v., oral and p.v. administration of DS-1226as well as the factors on their bioavailabilities were investigated. Meanwhile, the permeability through the small intestine and the BBB were also studied by using the Caco-2cell model and in vitro BBB model, respectively. Finally, potentially drug interaction of DS-1226was investigated. PPT, which structure only differs from PPD by a hydroxyl group at the C-6position, showed quite different pharmacokinetic properties from PPD, the bioavailability of PPD was relatively higher than PPT both in plasma and brain. The present study could provide ideas for further research and development of ginsenoside aglycones, so as to further study their mechanisms and to evaluate their druggabilities.
1、本文首先建立了同时测定生物样品(血浆、皮层和海马)中PPT和PPD的高效,灵敏,稳定可靠的LC-MS分析方法。本方法以齐墩果酸作为内标,采用二氯甲烷液液萃取方法处理生物样品,在流动相中加入0.05mmol/L氯化铵以提高检测灵敏度,采用加氯母离子m/z511.6(PPT), m/z495.9(PPD), m/z455.5(OA,内标)作为检测离子。结果显示,血浆样品和海马匀浆液中PPT和PPD的最低检测限均为10.0ng/mL,最低定量限均为20.0ng/mL。皮层匀浆液中PPT和PPD的最低检测限为3.3ng/mL,最低定量限为6.7ng/mL。对日内、日间精密度和准确度进行了考察,结果表明此方法的精密度和准确度均符合生物样品分析的要求。
2、应用新建立的LC-MS分析方法,对静脉(30mg/kg)、口服(75mg/kg)和肝门静脉(75mg/kg)等不同途径给予DS—1226后其主要成分PPT和PPD在大鼠体内的药代动力学特性进行研究,同时对PPT和PPD的胃肠道稳定性进行研究。体内药代动力学实验结果表明,口服给药后PPT和PPD的tmax,t1/2分别为0.58h,0.95h和1.82h,3.76h,表明PPT的达峰时间和体内消除速度相对于PPD均较快。PPT的口服生物利用度很低,仅为3.69%,而PPD具有较好的生物利用度,为48.12%。肝门给药时PPT和PPD的生物利用度分别为101.27%和100.54%,表明不存在肝首过效应,说明肝首过效应不是导致PPT生物利用度低的原因。静脉给药后PPT和PPD可进入脑组织,且在海马中含量较皮层中高。胃肠道稳定性研究结果显示,PPT在pH1.2缓冲液、胃内容物中发生明显的降解,推测其在胃中不稳定性可能是导致其生物利用度低的原因之一。
3、本文在建立体外Caco-2细胞摄取、转运模型的基础上,对PPT和PPD的肠吸收机理进行了研究。结果表明,PPT和PPD在不同浓度(10,20,40μM)下表观渗透系数(Papp AP→BL)分别为(12.40～15.35)×10-6cm/s和(22.71～25.80)×10一cm/s,均属于吸收良好的药物。从AP→BL及BL→AP的转运量随浓度的增高而相应增大,而Papp值基本保持不变,外排比率均小于1.5。加入100μM维拉帕米后,PPT和PPD的Papp AP→BL与不加抑制剂组相比均无显著性差异,表明PPT和PPD在肠道上的转运方式均为被动扩散。
4、本文采用分离、纯化得到的原代大鼠脑微血管内皮细胞和星形胶质细胞通过共培养方式建立体外血脑屏障模型,然后对PPT、PPD的透血脑屏障能力进行考察。实验结果显示,PPT和PPD在不同浓度(10,20,40μM)下表观渗透系数(Papp AP→BL)分别为(30.30～34.39)×10-6cm/s和(4.09～5.08)×10-6cm/s。PPT的Papp值比PPD高约8倍,表明PPT相对于PPD更容易透过血脑屏障。
5、最后,本文采用Cocktail探针底物法和Rho-123摄取法分别评价DS-1226对肝微粒体CYP450酶和P-糖蛋白(P-glycoprotein, P-gP)活性的影响。结果显示DS-1226对CYP3A4介导的睾酮6p-羟基化反应抑制最强,IC50为7.58μg/mL。对CYP2C19介导的奥美拉唑5-羟基化和CYP2C9介导的甲苯磺丁脲4。羟基化也有较强的抑制作用,IC50分别为13.28μg/mL和9.69μg/mL。对CYP2E1介导的氯挫沙宗6-羟基化和CYP2D6介导的右美沙芬O-脱烷基化则几乎无抑制作用,IC50分别为99.48μg/mL和114.90μg/mL。提示DS-1226有可能在体内通过抑制肝脏CYP酶而引起显著的药物相互作用。同时DS-1226对P-gp的有一定的抑制作用,但与阴性对照组无显著性差异(P>0.05)。
总之,本文通过静脉、口服、肝门静脉等不同给药途径给予DS-1226后研究PPT和PPD的体内药代动力学特性,并对影响其生物利用度的因素进行了探讨；同时,分别采用Caco-2细胞模型和体外血脑屏障模型对PPT和PPD单体的肠吸收机制和透血脑屏障能力进行了研究；最后,对DS-1226潜在的药物相互作用进行了初步研究。PPT仅比PPD在C-6多了一个羟基,但是二者的药动学特性表现出很大差异,PPD无论在血液循环系统还是脑组织中均具有较高的利用率。本研究为人参皂苷元类化合物的进一步研究和开发利用提供了思路,以便后续更深入的探讨其作用机制以及对其成药性做出评价。
Based on their chemical structures, ginsenosides are divided into three groups:protopanaxatriol (PPT), protopanaxadiol (PPD) and oleanane types. Ginsenosides had been found a wide range of biological activities, including immunomodulatory, anti-tumor, learning and memory improving, anti-aging, antiinflammatory, antidementia, antifatigue, hemopoietic function promotion and so on. However, ginsenosides themselves can not easily be absorbed and their bioavailabilities were poor. Many studies demonstrated that ginsenosides can be hydrolyzed in the gastrointestinal (GI) tract to form their metabolites including PPT and PPD, which are more easily absorbed into the body and displayed more potent activities than ginsenosides. Dammarane Sapogenins (DS-1226), which was prepared by proprietary technology to alkaline hydrolysis of total ginsenosides derived from the stem and leaf of Panax ginseng. This production and technology has already won patent rights at eight countries or regions, including China, USA, Canada, European Union, Taiwan, etc. DS-1226was mainly composed of33%PPT and16%PPD, and had been found with significant activities in improving learning and memory on cognitive dysfunction caused by sleep interruption in mice, and also decreasing chemotherapy-induced myelosuppression. In present study, we investigated the pharmacokinetic properties of PPT and PPD in rat plasma and brain using a LC-MS method when DS-1226was administrated to rats. The permeability through the small intestine and the blood-brain-barrier (BBB) were studied by using the Caco-2cell model and in vitro blood-brain barrier model, respectively. Finally, potentially drug-drug interaction of DS-1226was investigated.
1. A sensitive LC-MS method was developed for the simultaneous determination of PPT and PPD in rat plasma and brain tissue. The analytes were extracted with dichloromethane and using OA as an internal standard. In order to achieve the abundant and stable signals,0.05mmol/L ammonium chloride was added to the mobile phase, and the chloride adducted molecule ions [M+C1]-at m/z511.6,495.9and455.5were used for monitoring PPT, PPD and OA, respectively. The results indicated that the limits of detection and quantification for both PPT and PPD in rat plasma and hippocampal were10.0,20.0ng/ml, respectively. And both the limits of detection, quantification for PPT and PPD in rat cortex were3.3ng/ml,6.7ng/ml, respectively. The intra-day and inter-day precisions and the accuracies were satisfactory and indicated that the LC-MS method was suitable for biological analysis.
2. The pharmacokinetics of PPT and PPD in rats were studied after intravenously (i.v.,30mg/kg), oral (75mg/kg) and portal vein (p.v.,75mg/kg) administration of DS-1226. Their in vitro stabilities in the gastrointestinal (GI) tract were also investigated. The results showed that PPT was rapid absorption and eliminated rapidly from the body with averagetmax value of0.58h and t1/2,λz of0.95h after oral administration, while PPD was absorption and eliminated relatively slowly with tmax value of1.82h and t1/2,λz of3.76h. The absolute bioavailabilities of PPT and PPD were estimated as3.69%and48.12%, respectively.DS-1226was administrated to rats through the hepatic portal vein for exploring the hepatic first-pass effect of PPT and PPD. The results showed that the bioavailabilities of PPT and PPD were101.27%and100.54%, which indicated that hepatic first-pass should not be the reason for its low bioavailabilitiy. Both PPT and PPD could be detected in brain after i.v. administration, and their concentrations in hippocampal were relatively higher than that in cortex. The stability test found that PPT was instable both in pH1.2buffer and in the stomach content solution, indicated that the instability in the stomach might be one of the reasons for PPT poor bioavailabilitiy.
3. Their intestinal transport absorption were investigated by using the Caco-2cell monolayer model. The results showed that PPT and PPD at three concentrations (10,20and40μM) have good absorption transport with Papp AP→BL value of (12.40～15.35)×10-6cm/s and (22.71～25.80)×10-6cm/s. The transported amounts of PPT and PPD were all increased with the increase of loading concentrations, with no changes for Papp values, the ratios of Papp BL→AB/Papp AB→BL for PPD and PPT were less than1.5. Furthermore, the Papp values for PPD and PPT were determined in the presence of100μM verapamil, and were found similar with that of absence of verapamil. This suggests that passive diffusion is the main transport mechanism of both PPD and PPT.
4. In vitro BBB model by co-culture primary cultured brain endothelial cells and astrocytes was established, and permeability of PPT and PPD through BBB were investigated. The results showed that PPT and PPD at three concentrations (10,20and40μM) both could penetrate the BBB, and with PappAP→BL value of (30.30～34.39)×10-6cm/s and (4.09～5.08)×10-6cm/s. The Papp values for PPT was about eight times higher than that for PPD, which indicated that PPT could be penetrate the BBB more easily.
5. Finally, the inhibitory effect of DS-1226on the activities of hepatic microsomal CYP450enzymes were investigated by cocktail probe drugs, and the effect of DS-1226on the activity of P-gp was investigated by uptake of Rho-123. The results showed that DS-1226have significant inhibiting effects on the activity of CYP3A4, CYP2C9and CYP2C19, with the IC50value of7.58,9.69and13.28μg/mL, while the inhibiting effects on the activity of CYP2E1and CYP2D6were relatively weakly, with the IC50value of99.48μM and114.90μM. The results indicate that DS-1226might cause significant drug interactions by inhibiting hepatic CYP450enzymes in vivo. DS-1226has weak inhibition on P-gp, but there was no significant difference between DS-1226groups and negative control group (P>0.05).
In conclusion, the pharmacokinetic properties of PPT and PPD after i.v., oral and p.v. administration of DS-1226as well as the factors on their bioavailabilities were investigated. Meanwhile, the permeability through the small intestine and the BBB were also studied by using the Caco-2cell model and in vitro BBB model, respectively. Finally, potentially drug interaction of DS-1226was investigated. PPT, which structure only differs from PPD by a hydroxyl group at the C-6position, showed quite different pharmacokinetic properties from PPD, the bioavailability of PPD was relatively higher than PPT both in plasma and brain. The present study could provide ideas for further research and development of ginsenoside aglycones, so as to further study their mechanisms and to evaluate their druggabilities.
引文
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