柴胡疏肝散抗氧化活性及其活性成分柚皮苷药代动力学的研究
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摘要
柴胡疏肝散(CSGS)是中国传统经典方剂,由七味药材组成,具有疏肝解郁,活血止痛的功效,临床上用于治疗消化系统、神经系统、心血管系统及妇科等各类疾病,药理研究表明其具有抗抑郁作用。当今,人们面临着来自各方面的巨大的精神压力,抑郁症已成为困扰我国的第二大类疾病。为进一步阐释CSGS抗抑郁的药理作用机制及物质基础,论文研究了柴胡疏肝散的体内外抗氧化活性,探讨抗氧化活性与抗抑郁作用之间的联系。并对复方中抗抑郁活性成分柚皮苷(NA)进行了药代动力学研究,考察复方中柚皮苷及单体柚皮苷在大鼠体内代谢规律的差异。
实验采用六种方法,评价CSGS水提物体外抗氧化活性。CSGS体外具有一定的铁离子还原能力和自由基清除能力,其还原能力即总抗氧化能力相当于0.24 mmol FeSO4每克复方水提物,清除DPPH(1,1-二苯基-2-苦基苯肼)自由基、ABTS[2,2-连氮(3-乙基苯并噻唑啉-6-磺酸)二铵盐]阳离子自由基、O2·-(超氧阴离子)及·OH(羟自由基)的IC50分别为0.83 mg·mL-1、1.03 mg·mL-1、10.31 mg·mL-1、7.79 mg·mL-1,氧自由基吸收能力ORAC值为1.50±0.19μmol Trolox／mg。建立氧化应激模型,通过测定全血中谷胱甘肽(GSH)含量,肝组织中超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、丙二醛(MAD)含量考察CSGS对束缚导致氧化应激反应小鼠的体内作用。在束缚应激状态下,CSGS能显著改善机体中SOD及CAT活性,提高GSH含量,增强机体抗氧水平,抑制脂质过氧化,降低脂质代谢物MDA的含量。
柚皮苷(NA)为CSGS中入血的抗抑郁活性成分之一,实验采用LC-MS/MS建立专属性检测方法快速定量大鼠血清中药物含量。通过对大鼠口服CSGS水提物(2.5 g·kg-1)及方中相同剂量的单体NA (5.075 mg·kg-1)后的血清样品进行含量测定,发现两者血药浓度-时间关系曲线均呈现双峰现象,CSGS中两次达峰时间较NA向后推迟,表明NA的体内代谢可能存在肝肠循环。用药代动力学软件WinNonlin对所得数据进行分析,CSGS和NA单体的消除半衰期分别为171.8932min和255.7001min表明复方中NA比NA单体消除快,不易滞留,毒副作用小。两者进入血循环总量分别为840.2175 min*mg/L和114.0243 min*mg/L,表明复方中NA入血起效量较多,生物利用度更高。两者持续时间分别为523.3516min,274.8070 min,说明复方中的NA药效更为持久。
柴胡疏肝散可清除过氧自由基,抑制脂质过氧化反应,缓解氧化应激损伤,提高机体抗氧化能力,CSGS抗抑郁作用的发挥可能部分来自其抗氧化活性的贡献。复方中柚皮苷及单体柚皮苷在大鼠体内药物代谢的差异表明,复方中单体利用度更高、毒副作用小、疗效更为持久,也说明了复方组方用药的合理性。
Chaihu-Shu-Gan-San (CSGS), a classical traditional Chinese herbal formula consisting of seven herbal medicines has been applied to relieve stagnancy in liver and promote blood circulation to alleviate pain in China. It has been widely used in clinical treatment of various diseases in digestive system, neural system, cadiovascular system, gynaecology and et al. Pharmacological researches confirmed that CSGS provided with antidepressive effect. Nowadays, people have to face all kinds of tremendous mental stresses, which lead to the possible result that depression had been attested to be the second disease threatened the health of Chinese people. In order to clarify the possible mechanism and material basis of CSGS antidepressive efficacy, we carried out the studies on antioxidant activity of CSGS to understand the relationship between its antioxidant properties and antidepressive effect and pharmacokinetics of antidepressive ingredient Naringin (NA) in CSGS to compare the differences of metabolism in rats between NA in CSGS and NA monomer.
The antioxidant activity in vitro was evaluated by employing six antioxidant assays. CSGS showed a ferric reducing antioxidant power that was equivalent to 0.24 mmol FeSO4 per gram CSGS aqueous extract and certain scavenging activities on free radicals. The IC50 values of CSGS in scavenging DPPH radicals, ABTS cation radicals, O2'-(superoxide anion) and·OH (hydroxyl free radicals) were 0.83 mg·mL-1,1.03 mg·mL-1,10.31 mg·mL-1 and 7.79 mg·mL-1, respectively. The ORAC value of oxygen radical absorbance capacity was 1.50±0.19μmol Trolox/mg. The in vivo study was carried out to investigate the effect of CSGS on mice in restraint stress model by determining glutathione (GSH) contents in blood and malondialdehyde (MDA) values, superoxide dismutase (SOD) and catalase (CAT) activities in liver. Under restraint stress, CSGS could significantly improve activities of SOD and CAT, increase content of GSH to enhance antioxidant capacity of the organism, as well as inhibit lipid peroxidation to decrease content of MDA.
NA is one of the active and aitidepressive ingredients in the prescription. A specific LC-MS/MS method was built up for fast quantitative analysis of NA using intenal standard substance. Double peaks phenomenon was observed in both serum concentration-time profiles of rats after orally administered CSGS aqueous extract (2.5 g·kg-1) and the same amount of pure NA (5.075 mg·kg-1) as in CSGS, which manifested that metabolism of NA may experience enterohepatic circulation. Pharmacokinetics was analyzed using the non-compartmental model of the software-WinNonlin. Terminal elimination half-life of CSGS and NA were 171.8932 min and 255.7001 min respectively, which indicated that NA in CSGS was better than NA monomer with fast elimination, short time accumulation and small toxic and side-effect. AUCall of CSGS and NA were 840.2175 min*mg/L and 114.0243 min*mg/L respectively. The data showed that there was more NA in the prescription absorbed into blood circulation, so CSGS had higher bioavailability. And the mean residence time of the two were 523.3516 min and 274.8070 min, which manifested that the prescription had long term efficacy.
CSGS exhibited the ability of eliminating free radicals, inhibiting lipid peroxidation, relieving oxidative injury and regulating antioxidant capacity of organisms, which may make contributions to its antidepressive effect. Differences of pharmacokinetic study in rats between NA in CSGS and NA monomer showed that NA in the prescription had long term efficacy, high bioavailability and low toxic side-effect which the monomer could not come up to and confirmed that herbal combination in CSGS was rational.
实验采用六种方法,评价CSGS水提物体外抗氧化活性。CSGS体外具有一定的铁离子还原能力和自由基清除能力,其还原能力即总抗氧化能力相当于0.24 mmol FeSO4每克复方水提物,清除DPPH(1,1-二苯基-2-苦基苯肼)自由基、ABTS[2,2-连氮(3-乙基苯并噻唑啉-6-磺酸)二铵盐]阳离子自由基、O2·-(超氧阴离子)及·OH(羟自由基)的IC50分别为0.83 mg·mL-1、1.03 mg·mL-1、10.31 mg·mL-1、7.79 mg·mL-1,氧自由基吸收能力ORAC值为1.50±0.19μmol Trolox／mg。建立氧化应激模型,通过测定全血中谷胱甘肽(GSH)含量,肝组织中超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、丙二醛(MAD)含量考察CSGS对束缚导致氧化应激反应小鼠的体内作用。在束缚应激状态下,CSGS能显著改善机体中SOD及CAT活性,提高GSH含量,增强机体抗氧水平,抑制脂质过氧化,降低脂质代谢物MDA的含量。
柚皮苷(NA)为CSGS中入血的抗抑郁活性成分之一,实验采用LC-MS/MS建立专属性检测方法快速定量大鼠血清中药物含量。通过对大鼠口服CSGS水提物(2.5 g·kg-1)及方中相同剂量的单体NA (5.075 mg·kg-1)后的血清样品进行含量测定,发现两者血药浓度-时间关系曲线均呈现双峰现象,CSGS中两次达峰时间较NA向后推迟,表明NA的体内代谢可能存在肝肠循环。用药代动力学软件WinNonlin对所得数据进行分析,CSGS和NA单体的消除半衰期分别为171.8932min和255.7001min表明复方中NA比NA单体消除快,不易滞留,毒副作用小。两者进入血循环总量分别为840.2175 min*mg/L和114.0243 min*mg/L,表明复方中NA入血起效量较多,生物利用度更高。两者持续时间分别为523.3516min,274.8070 min,说明复方中的NA药效更为持久。
柴胡疏肝散可清除过氧自由基,抑制脂质过氧化反应,缓解氧化应激损伤,提高机体抗氧化能力,CSGS抗抑郁作用的发挥可能部分来自其抗氧化活性的贡献。复方中柚皮苷及单体柚皮苷在大鼠体内药物代谢的差异表明,复方中单体利用度更高、毒副作用小、疗效更为持久,也说明了复方组方用药的合理性。
Chaihu-Shu-Gan-San (CSGS), a classical traditional Chinese herbal formula consisting of seven herbal medicines has been applied to relieve stagnancy in liver and promote blood circulation to alleviate pain in China. It has been widely used in clinical treatment of various diseases in digestive system, neural system, cadiovascular system, gynaecology and et al. Pharmacological researches confirmed that CSGS provided with antidepressive effect. Nowadays, people have to face all kinds of tremendous mental stresses, which lead to the possible result that depression had been attested to be the second disease threatened the health of Chinese people. In order to clarify the possible mechanism and material basis of CSGS antidepressive efficacy, we carried out the studies on antioxidant activity of CSGS to understand the relationship between its antioxidant properties and antidepressive effect and pharmacokinetics of antidepressive ingredient Naringin (NA) in CSGS to compare the differences of metabolism in rats between NA in CSGS and NA monomer.
The antioxidant activity in vitro was evaluated by employing six antioxidant assays. CSGS showed a ferric reducing antioxidant power that was equivalent to 0.24 mmol FeSO4 per gram CSGS aqueous extract and certain scavenging activities on free radicals. The IC50 values of CSGS in scavenging DPPH radicals, ABTS cation radicals, O2'-(superoxide anion) and·OH (hydroxyl free radicals) were 0.83 mg·mL-1,1.03 mg·mL-1,10.31 mg·mL-1 and 7.79 mg·mL-1, respectively. The ORAC value of oxygen radical absorbance capacity was 1.50±0.19μmol Trolox/mg. The in vivo study was carried out to investigate the effect of CSGS on mice in restraint stress model by determining glutathione (GSH) contents in blood and malondialdehyde (MDA) values, superoxide dismutase (SOD) and catalase (CAT) activities in liver. Under restraint stress, CSGS could significantly improve activities of SOD and CAT, increase content of GSH to enhance antioxidant capacity of the organism, as well as inhibit lipid peroxidation to decrease content of MDA.
NA is one of the active and aitidepressive ingredients in the prescription. A specific LC-MS/MS method was built up for fast quantitative analysis of NA using intenal standard substance. Double peaks phenomenon was observed in both serum concentration-time profiles of rats after orally administered CSGS aqueous extract (2.5 g·kg-1) and the same amount of pure NA (5.075 mg·kg-1) as in CSGS, which manifested that metabolism of NA may experience enterohepatic circulation. Pharmacokinetics was analyzed using the non-compartmental model of the software-WinNonlin. Terminal elimination half-life of CSGS and NA were 171.8932 min and 255.7001 min respectively, which indicated that NA in CSGS was better than NA monomer with fast elimination, short time accumulation and small toxic and side-effect. AUCall of CSGS and NA were 840.2175 min*mg/L and 114.0243 min*mg/L respectively. The data showed that there was more NA in the prescription absorbed into blood circulation, so CSGS had higher bioavailability. And the mean residence time of the two were 523.3516 min and 274.8070 min, which manifested that the prescription had long term efficacy.
CSGS exhibited the ability of eliminating free radicals, inhibiting lipid peroxidation, relieving oxidative injury and regulating antioxidant capacity of organisms, which may make contributions to its antidepressive effect. Differences of pharmacokinetic study in rats between NA in CSGS and NA monomer showed that NA in the prescription had long term efficacy, high bioavailability and low toxic side-effect which the monomer could not come up to and confirmed that herbal combination in CSGS was rational.
引文
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