丹芎方及其活性主成分的药效学、药动学及其相互作用
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摘要
本研究将丹参水溶性活性组分(药效学和药动学研究均以丹参素为定量标准)、丹参脂溶性活性组分(药效学研究以所含总丹参酮为定量标准、药动学研究以丹参酮中含量最高的隐丹参酮为定量标准)和川芎中主要活性成分阿魏酸(药效学和药动学均以阿魏酸为定量标准)按照不同的比例形成6个不同的复方制剂,称为丹芎方(DanXiongFang,DXF)1、2、3、4、5、6号,应用高脂饲料诱发的C57BL/6J小鼠髙脂模型筛选出其中降脂效果良好的1、4号,在此基础上进行了一系列的药效学和药动学研究。
1.丹芎方的降脂作用应用高脂饲料饲喂4周建立高脂血症大鼠模型,然后连续给予洛伐他汀(7mg/kg)、考莱烯胺(1300mg/kg)、DXF1高、中、低(330、66、13mg/kg)剂量4周,采血检测血清TC、TG、HDL、LDL、ALT、白蛋白。结果表明,和正常组相比,给予高脂饲料后大鼠血浆TC(2.08±0.24 vs 16.07±4.13mmol/L)、LDL(0.42±0.10 vs 7.57±2.33mmol/L)、TG(0.74±0.10 vs 1.18±0.71mmol/L )、转氨酶均显著升高。DXF1大剂量组血浆TC为6.78±3.82mmol/L,较洛伐他汀(13.04±4.60mmol/L)疗效好,与考莱烯胺(8.43±4.64mmol/L)相当,DXF1中、小剂量组TC虽有下降,但是与模型组相比没有显著性差异,LDL的结果相似。各药物组均可显著降低TG,值得注意的是DXF1小剂量对TG的降低效果强于高、中剂量,此外各药物均可显著降低转氨酶,提示DXF具有良好的降低TC、LDL和TG的作用,小剂量降低TG作用最突出。
2.丹芎方的保肝作用采用小鼠腹腔注射CCl4制作肝脏损伤模型,通过测定小鼠血清中ALT、AST、总蛋白、白蛋白、白球蛋白比和肝脏组织中SOD、MDA等指标,研究DXF4-1、2、3、4剂量组(247.1、49.42、9.88、1.97mg/kg),丹参水溶性组分(丹参素20.7mg/kg),丹参脂溶性组分(总丹参酮12.6mg/kg),阿魏酸16.12mg/kg,以及联苯双酯滴丸25.6mg/kg对小鼠CCl4肝损伤模型的保护作用。结果表明DXF4各剂量和各组分均可非常显著抑制CCl4损伤后血浆中ALT和AST,能够将其降低至正常水平,提高血清和肝脏中SOD活性,减少MDA形成,升高血浆中总蛋白、白蛋白、球蛋白水平。DXF4-4的总剂量远远低于其它DXF剂量组和任何一个单组分的剂量,但是疗效与其相当,提示DXF不仅具有明显的保肝作用,并且有一定的药效学优化作用。
3.丹芎方的抗炎作用采用蛋清所致足趾肿胀实验、羧甲基纤维素所致白细胞游走实验、棉球植入腹腔所致肉芽肿实验观察DXF1 330、66、13mg/kg的抗炎作用,阳性药醋酸泼尼松1mg/kg。结果表明DXF1能有效减轻蛋清所致大鼠足趾肿胀,DXF1各剂量组均较醋酸泼尼松起效快,其中DXF1中剂量最快,1h即可显著减轻肿胀。针对后两种模型,DXF1高、中剂量和阳性药具有显著疗效,DXF1中剂量疗效优于大剂量,DXF1小剂量无效。提示DXF具有一定的抗炎作用。
4.丹芎方对缺氧脑组织的保护作用小鼠60只,随机分为正常对照组、常压低氧模型组、普萘洛尔组12mg/kg、DXF4 120、60、30mg/kg,连续灌胃7d后,测定小鼠在常压低氧状态下的存活时间,测定脑匀浆的SOD、NOS、MDA、Lac(乳酸)含量。结果表明DXF4 120mg/kg可以显著延长常压低氧状态小鼠的存活时间,各个药物组均可显著提高SOD活力;降低NOS活力;降低MDA、Lac含量。表明DXF可显著减轻常压缺氧小鼠脑组织的氧化损伤,具有一定的延长小鼠存活时间的保护作用。
5.丹芎方活性主成分在兔静脉给药后的药动学及相互作用建立灵敏、可靠可同时测定丹参素、阿魏酸和隐丹参酮的HPLC/DAD方法,应用此方法进行了兔静脉给予丹参水溶性组分、脂溶性组分、阿魏酸及DXF(丹参素:阿魏酸:隐丹参酮为1:1:1)后,几个目标化合物在兔体内的动力学过程以及组分之间药动学相互作用的研究。结果表明,丹参素、阿魏酸与隐丹参酮在单组分和复方给药情况下体内的血药经时过程均符合静脉给药二室开放模型。丹参素、阿魏酸在兔体内的分布过程和消除过程都比较快,t1/2а分别为2.84±2.00min和1.47±1.30min,t1/2β分别为20.95±10.18min和19.28±10.21min,隐丹参酮的分布过程也很快t1/2а为2.13±0.72min,但是消除过程明显慢于丹参素和阿魏酸,t1/2β为69.69±27.22min,复方给药对丹参素和阿魏酸的分布和消除过程没有明显影响,但是将隐丹参酮的t1/2β延长至85.01±42.46min。阿魏酸和隐丹参酮的AUC在复方给药后从94.33±27.65μg·min/ml和80.49±19.21μg·min/ml增加到122.05±48.92μg·min/ml和129.34±44.74μg·min/ml。提示DXF复方给药可能对其中几个组分中的目标化合物具有一定的药动学优化作用的潜能。
6.丹芎方及其活性主成分在原位大鼠肠灌流模型中的吸收特征及相互作用建立大鼠原位肠灌流模型,采用循环灌流方式,经肠切口给予DXF4(164mg/kg)、丹参水溶性组分(丹参素69 mg/kg)、阿魏酸(阿魏酸53.7 mg/kg)、丹参脂溶性组分(总丹参酮42.5 mg/kg),于给药后0、45和90 min采样后经LC-MS检测。结果显示,与等剂量各单组分给药相比,DXF4复方给药后能够显著促进丹参素的肠道吸收,但是对阿魏酸和隐丹参酮的吸收过程没有明显影响。
Our lab had designed a series of new Chinese medical complex prescription, which was composed by water soluble components from danshen, liposoluble conmponents from danshen and ferulic acid from Chuanxiong. It was named by DanXiongFang1, 2, 3, 4, 5, 6 (DXF1, 2, 3, 4, 5, 6). In order to convenient for quality control, we had selected danshensu as the target chemical of water-soluble components, total tanshinone as the pharmacodynamic target and cryptotanshinone as the pharmacokinetic target of the liposoluble conmponents from danshen. We had carried out a preliminary pharmacodynamic screen of the prescription with C57BL/6J hyperlipidemia model induced by high-lipid diet, and selected DXF1and DXF4, then a series of pharmacodynamic and pharmacokinetic study was carried out.
1.Effect of Danxiongfang on reducing serum lipids level in rat model with hyperlipidemia induced by high-lipid diet: The rats were fed with high-fat diet for 4 weeks to establish the hyperlipidemic model, then lovastatin(7mg/kg), cholestyramine(1300mg/kg), DXF1 330, 66, and 13mg/kg were given to the rats orally for 4 weeks. The serum TG, TC, HDL, LDL, ALT, albumin were detected at the end of 4 weeks. The results showed that the rats developed hyperlipidemia with high serum lipid levels (TC: 2.08±0.24 vs 16.07±4.13mmol/L; LDL: 0.42±0.10 vs 7.57±2.33 mmol/L; TG: 0.74±0.10 vs 1.18±0.71mmol/L), serum ALT and albumin concentration also increased significantly. DXF1 330mg/kg could decrease the serum TC to 6.78±3.82mmol/L, better than lovastatin (13.04±4.60mmol/L) and similar to cholestyramine (8.43±4.64mmol/L). There showed similar effect on LDL. It is noteworthy that DXF1 13mg/kg showed the strongest inhibitory effect on serum TG levels. At the same time they all could decrease the ALT level and increase serum albumin level. A conclusion could be drawn that DXF posses powerful lipid regulating and liver protective effect.
2.Effect of DXF and its active components on Experimental liver injury models induced by CCl4 in mice: Mice are injected with CCl4 to establish liver injured model. ALT, AST, serum albumin, globulin in serum and SOD, MDA in liver are measured to confirm the ability of protecting liver of DXF4 (247.1, 49.42, 9.88, 1.97mg/kg), water-soluble components 20.7mg/kg, liposoluble components 12.6mg/kg,ferulic acid 16.12mg/kg. Bifendate pills was selected as positive drug, its dose was 25.6mg/kg. The results showed DXF4 and all components could inhibit obviously the abnormal increase of ALT, AST in serum and MDA in liver, enhance SOD activity in liver, total protein, albumin, globulin in serum. DXF4 247.1 and 1.97mg/kg exhibited the strongest effect. The results suggested that DXF4 not only posses the potentialities of protecting injured liver induced by CCl4, but also optimize the action.
3.Anti-inflammatory effect of DXF: Set up acute animal models, such as egg white induced paw oedema in rat, sodium carboxymety-lcellulose (CMC-Na) induced air pouch leukocyte migration in rat, and a chronic inflammatory reaction model placing cottons into abdominal cavity of rats to induce granuloma to test anti-inflammatory activity of DXF1 (330, 66, 13mg/kg), prednisone acetate 1mg/kg was positive drug. The results showed that DXF1 330, 66mg/kg could inhibit paw oedema, leukocyte migration and the proliferation of granuloma, they took action faster than prednisone acetate. DXF1 66mg/kg had stronger effect than 330mg/kg, but 13mg/kg hadn’t exhibit any effect on three inflammatory models. The evidences suggested that DXF1 has definit anti-inflammatory effect.
4.Protective effect on brain in mice under normobaric hypoxia station: 60 mice were divided randomly and equally into 6 groups, they were control group, model group, propranolol group(12mg/kg) and DXF4 groups(160, 60, 30mg/kg), All reagents were given intra-gastrically into each mouse once a day for 7 days, at last day of the study, the mouse was put into a sealed bottle to observe the survival time of the mouse, the levels of MDA, SOD, Lac and NOS in the brain were detected with test kit. The results showed that DXF4 160mg/kg could prolong the survival time of the mouse significantly; but all groups could obviously inhibit the abnormal increase of MDA and Lac in brain, and reduce NOS activity in brain, and enhance SOD activity in brain. These results showed that DXF4 posses the protective effect against brain injury under normobaric hypoxia station.
5.Pharmacokinetic characteristics and interaction of main active components in DXF: A new RP-HPLC/DAD method was established to simultaneously determine the biomarker content of danshensu, ferulic acid and cryptotanshinone in DXF. Then the pharmacokinetics characteristics of the main active components danshensu, ferulic acid, cryptotanshinone in rabbits were investigated after i.v. administration any components alone or DXF by the method of HPLC. The pharmacokinetical results indicated that the plasma drug concentration-time curves of danshensu, ferulic acid and cryptotanshinone in rabbits were all best fitted to two-compartment open models after i.v. component alone or DXF. The results showed that danshensu and ferulic acid were distributed and eliminated comparatively fast in rabbits, their t1/2αwere 2.84±2.00min and 1.47±1.30min, and t1/2βwere 20.95±10.18, 19.28±10.21min. The distribution process of cryptotanshinone was also fast, t1/2αwas 2.13±0.72min, but its elimination process was 3 times slower than danshensu and ferulic acid, its t1/2βwas 69.69±27.22min. Administration of compound prescription had no influences on distribution and elimination process within body of danshensu and ferulic acid, but it could prolong the t1/2βof cryptotanshinone to 85.01±42.46min. The AUC of ferulic acid and cryptotanshinone were obviously improved from 94.33±27.65μg·min/ml and 80.49±19.21μg·min/ml to 122.05±48.92μg·min/ml and 129.34±44.74μg·min/ml. As a conclusion it can be said that DXF could optimize the pharmacokinetic process in vivo of target chemicals from those components.
6.Absorption characteristics and interaction of DXF and its main active components: In order to study the absorption characteristics of DXF4 and its components, we established a model of in situ perfused rat intestine preparation and a HPLC-MS method to determine the concentration of danshensu, ferulic acid and cryptotanshinone. The dose of DXF4 was 164mg/kg (danshensu 69 mg/kg, ferulic acid 53.7 mg/kg, total tanshinone 42.5 mg/kg), the doses of components in DXF4 were similar to that in DXF4. 200μl samples were collected at 15, 45 and 90 minute, the concentration of target chemicals were detected by HPLC-MS. The results showed that DXF4 have no effect on absorptive permeability of ferulic acid and cryptotanshinone, but can increase the absorptive permeability of danshensu.
1.丹芎方的降脂作用应用高脂饲料饲喂4周建立高脂血症大鼠模型,然后连续给予洛伐他汀(7mg/kg)、考莱烯胺(1300mg/kg)、DXF1高、中、低(330、66、13mg/kg)剂量4周,采血检测血清TC、TG、HDL、LDL、ALT、白蛋白。结果表明,和正常组相比,给予高脂饲料后大鼠血浆TC(2.08±0.24 vs 16.07±4.13mmol/L)、LDL(0.42±0.10 vs 7.57±2.33mmol/L)、TG(0.74±0.10 vs 1.18±0.71mmol/L )、转氨酶均显著升高。DXF1大剂量组血浆TC为6.78±3.82mmol/L,较洛伐他汀(13.04±4.60mmol/L)疗效好,与考莱烯胺(8.43±4.64mmol/L)相当,DXF1中、小剂量组TC虽有下降,但是与模型组相比没有显著性差异,LDL的结果相似。各药物组均可显著降低TG,值得注意的是DXF1小剂量对TG的降低效果强于高、中剂量,此外各药物均可显著降低转氨酶,提示DXF具有良好的降低TC、LDL和TG的作用,小剂量降低TG作用最突出。
2.丹芎方的保肝作用采用小鼠腹腔注射CCl4制作肝脏损伤模型,通过测定小鼠血清中ALT、AST、总蛋白、白蛋白、白球蛋白比和肝脏组织中SOD、MDA等指标,研究DXF4-1、2、3、4剂量组(247.1、49.42、9.88、1.97mg/kg),丹参水溶性组分(丹参素20.7mg/kg),丹参脂溶性组分(总丹参酮12.6mg/kg),阿魏酸16.12mg/kg,以及联苯双酯滴丸25.6mg/kg对小鼠CCl4肝损伤模型的保护作用。结果表明DXF4各剂量和各组分均可非常显著抑制CCl4损伤后血浆中ALT和AST,能够将其降低至正常水平,提高血清和肝脏中SOD活性,减少MDA形成,升高血浆中总蛋白、白蛋白、球蛋白水平。DXF4-4的总剂量远远低于其它DXF剂量组和任何一个单组分的剂量,但是疗效与其相当,提示DXF不仅具有明显的保肝作用,并且有一定的药效学优化作用。
3.丹芎方的抗炎作用采用蛋清所致足趾肿胀实验、羧甲基纤维素所致白细胞游走实验、棉球植入腹腔所致肉芽肿实验观察DXF1 330、66、13mg/kg的抗炎作用,阳性药醋酸泼尼松1mg/kg。结果表明DXF1能有效减轻蛋清所致大鼠足趾肿胀,DXF1各剂量组均较醋酸泼尼松起效快,其中DXF1中剂量最快,1h即可显著减轻肿胀。针对后两种模型,DXF1高、中剂量和阳性药具有显著疗效,DXF1中剂量疗效优于大剂量,DXF1小剂量无效。提示DXF具有一定的抗炎作用。
4.丹芎方对缺氧脑组织的保护作用小鼠60只,随机分为正常对照组、常压低氧模型组、普萘洛尔组12mg/kg、DXF4 120、60、30mg/kg,连续灌胃7d后,测定小鼠在常压低氧状态下的存活时间,测定脑匀浆的SOD、NOS、MDA、Lac(乳酸)含量。结果表明DXF4 120mg/kg可以显著延长常压低氧状态小鼠的存活时间,各个药物组均可显著提高SOD活力;降低NOS活力;降低MDA、Lac含量。表明DXF可显著减轻常压缺氧小鼠脑组织的氧化损伤,具有一定的延长小鼠存活时间的保护作用。
5.丹芎方活性主成分在兔静脉给药后的药动学及相互作用建立灵敏、可靠可同时测定丹参素、阿魏酸和隐丹参酮的HPLC/DAD方法,应用此方法进行了兔静脉给予丹参水溶性组分、脂溶性组分、阿魏酸及DXF(丹参素:阿魏酸:隐丹参酮为1:1:1)后,几个目标化合物在兔体内的动力学过程以及组分之间药动学相互作用的研究。结果表明,丹参素、阿魏酸与隐丹参酮在单组分和复方给药情况下体内的血药经时过程均符合静脉给药二室开放模型。丹参素、阿魏酸在兔体内的分布过程和消除过程都比较快,t1/2а分别为2.84±2.00min和1.47±1.30min,t1/2β分别为20.95±10.18min和19.28±10.21min,隐丹参酮的分布过程也很快t1/2а为2.13±0.72min,但是消除过程明显慢于丹参素和阿魏酸,t1/2β为69.69±27.22min,复方给药对丹参素和阿魏酸的分布和消除过程没有明显影响,但是将隐丹参酮的t1/2β延长至85.01±42.46min。阿魏酸和隐丹参酮的AUC在复方给药后从94.33±27.65μg·min/ml和80.49±19.21μg·min/ml增加到122.05±48.92μg·min/ml和129.34±44.74μg·min/ml。提示DXF复方给药可能对其中几个组分中的目标化合物具有一定的药动学优化作用的潜能。
6.丹芎方及其活性主成分在原位大鼠肠灌流模型中的吸收特征及相互作用建立大鼠原位肠灌流模型,采用循环灌流方式,经肠切口给予DXF4(164mg/kg)、丹参水溶性组分(丹参素69 mg/kg)、阿魏酸(阿魏酸53.7 mg/kg)、丹参脂溶性组分(总丹参酮42.5 mg/kg),于给药后0、45和90 min采样后经LC-MS检测。结果显示,与等剂量各单组分给药相比,DXF4复方给药后能够显著促进丹参素的肠道吸收,但是对阿魏酸和隐丹参酮的吸收过程没有明显影响。
Our lab had designed a series of new Chinese medical complex prescription, which was composed by water soluble components from danshen, liposoluble conmponents from danshen and ferulic acid from Chuanxiong. It was named by DanXiongFang1, 2, 3, 4, 5, 6 (DXF1, 2, 3, 4, 5, 6). In order to convenient for quality control, we had selected danshensu as the target chemical of water-soluble components, total tanshinone as the pharmacodynamic target and cryptotanshinone as the pharmacokinetic target of the liposoluble conmponents from danshen. We had carried out a preliminary pharmacodynamic screen of the prescription with C57BL/6J hyperlipidemia model induced by high-lipid diet, and selected DXF1and DXF4, then a series of pharmacodynamic and pharmacokinetic study was carried out.
1.Effect of Danxiongfang on reducing serum lipids level in rat model with hyperlipidemia induced by high-lipid diet: The rats were fed with high-fat diet for 4 weeks to establish the hyperlipidemic model, then lovastatin(7mg/kg), cholestyramine(1300mg/kg), DXF1 330, 66, and 13mg/kg were given to the rats orally for 4 weeks. The serum TG, TC, HDL, LDL, ALT, albumin were detected at the end of 4 weeks. The results showed that the rats developed hyperlipidemia with high serum lipid levels (TC: 2.08±0.24 vs 16.07±4.13mmol/L; LDL: 0.42±0.10 vs 7.57±2.33 mmol/L; TG: 0.74±0.10 vs 1.18±0.71mmol/L), serum ALT and albumin concentration also increased significantly. DXF1 330mg/kg could decrease the serum TC to 6.78±3.82mmol/L, better than lovastatin (13.04±4.60mmol/L) and similar to cholestyramine (8.43±4.64mmol/L). There showed similar effect on LDL. It is noteworthy that DXF1 13mg/kg showed the strongest inhibitory effect on serum TG levels. At the same time they all could decrease the ALT level and increase serum albumin level. A conclusion could be drawn that DXF posses powerful lipid regulating and liver protective effect.
2.Effect of DXF and its active components on Experimental liver injury models induced by CCl4 in mice: Mice are injected with CCl4 to establish liver injured model. ALT, AST, serum albumin, globulin in serum and SOD, MDA in liver are measured to confirm the ability of protecting liver of DXF4 (247.1, 49.42, 9.88, 1.97mg/kg), water-soluble components 20.7mg/kg, liposoluble components 12.6mg/kg,ferulic acid 16.12mg/kg. Bifendate pills was selected as positive drug, its dose was 25.6mg/kg. The results showed DXF4 and all components could inhibit obviously the abnormal increase of ALT, AST in serum and MDA in liver, enhance SOD activity in liver, total protein, albumin, globulin in serum. DXF4 247.1 and 1.97mg/kg exhibited the strongest effect. The results suggested that DXF4 not only posses the potentialities of protecting injured liver induced by CCl4, but also optimize the action.
3.Anti-inflammatory effect of DXF: Set up acute animal models, such as egg white induced paw oedema in rat, sodium carboxymety-lcellulose (CMC-Na) induced air pouch leukocyte migration in rat, and a chronic inflammatory reaction model placing cottons into abdominal cavity of rats to induce granuloma to test anti-inflammatory activity of DXF1 (330, 66, 13mg/kg), prednisone acetate 1mg/kg was positive drug. The results showed that DXF1 330, 66mg/kg could inhibit paw oedema, leukocyte migration and the proliferation of granuloma, they took action faster than prednisone acetate. DXF1 66mg/kg had stronger effect than 330mg/kg, but 13mg/kg hadn’t exhibit any effect on three inflammatory models. The evidences suggested that DXF1 has definit anti-inflammatory effect.
4.Protective effect on brain in mice under normobaric hypoxia station: 60 mice were divided randomly and equally into 6 groups, they were control group, model group, propranolol group(12mg/kg) and DXF4 groups(160, 60, 30mg/kg), All reagents were given intra-gastrically into each mouse once a day for 7 days, at last day of the study, the mouse was put into a sealed bottle to observe the survival time of the mouse, the levels of MDA, SOD, Lac and NOS in the brain were detected with test kit. The results showed that DXF4 160mg/kg could prolong the survival time of the mouse significantly; but all groups could obviously inhibit the abnormal increase of MDA and Lac in brain, and reduce NOS activity in brain, and enhance SOD activity in brain. These results showed that DXF4 posses the protective effect against brain injury under normobaric hypoxia station.
5.Pharmacokinetic characteristics and interaction of main active components in DXF: A new RP-HPLC/DAD method was established to simultaneously determine the biomarker content of danshensu, ferulic acid and cryptotanshinone in DXF. Then the pharmacokinetics characteristics of the main active components danshensu, ferulic acid, cryptotanshinone in rabbits were investigated after i.v. administration any components alone or DXF by the method of HPLC. The pharmacokinetical results indicated that the plasma drug concentration-time curves of danshensu, ferulic acid and cryptotanshinone in rabbits were all best fitted to two-compartment open models after i.v. component alone or DXF. The results showed that danshensu and ferulic acid were distributed and eliminated comparatively fast in rabbits, their t1/2αwere 2.84±2.00min and 1.47±1.30min, and t1/2βwere 20.95±10.18, 19.28±10.21min. The distribution process of cryptotanshinone was also fast, t1/2αwas 2.13±0.72min, but its elimination process was 3 times slower than danshensu and ferulic acid, its t1/2βwas 69.69±27.22min. Administration of compound prescription had no influences on distribution and elimination process within body of danshensu and ferulic acid, but it could prolong the t1/2βof cryptotanshinone to 85.01±42.46min. The AUC of ferulic acid and cryptotanshinone were obviously improved from 94.33±27.65μg·min/ml and 80.49±19.21μg·min/ml to 122.05±48.92μg·min/ml and 129.34±44.74μg·min/ml. As a conclusion it can be said that DXF could optimize the pharmacokinetic process in vivo of target chemicals from those components.
6.Absorption characteristics and interaction of DXF and its main active components: In order to study the absorption characteristics of DXF4 and its components, we established a model of in situ perfused rat intestine preparation and a HPLC-MS method to determine the concentration of danshensu, ferulic acid and cryptotanshinone. The dose of DXF4 was 164mg/kg (danshensu 69 mg/kg, ferulic acid 53.7 mg/kg, total tanshinone 42.5 mg/kg), the doses of components in DXF4 were similar to that in DXF4. 200μl samples were collected at 15, 45 and 90 minute, the concentration of target chemicals were detected by HPLC-MS. The results showed that DXF4 have no effect on absorptive permeability of ferulic acid and cryptotanshinone, but can increase the absorptive permeability of danshensu.
引文
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