氧化苦参碱的药代动力学、毒理学及药理作用
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摘要
氧化苦参碱为苦参和苦豆子的主要有效单体成分,在我国已有临床应用,具有抗炎、清除自由基、抑制肿瘤细胞增殖、改善胰岛素抵抗等多种药理作用,在老龄相关的代谢和认知功能退变中可能具有重要的临床应用前景。该文就氧化苦参碱在药代动力学、毒理学和药理方面的研究现状进行综述。
Oxymatrine,the main active monomer composition of Sophora flavescens and Sophoroa alopecuroides L., has been used in clinic in China with many pharmacological effects,such as anti-inflammation,scavenging free radicals,inhibiting tumor cell proliferation and improving insulin resistance. It may have important clinical application prospects in aging related metabol-ic and cognitive degeneration. This article reviews the current research status of oxymatrine in pharmacokinetics,toxicology and pharmacology.
Oxymatrine,the main active monomer composition of Sophora flavescens and Sophoroa alopecuroides L., has been used in clinic in China with many pharmacological effects,such as anti-inflammation,scavenging free radicals,inhibiting tumor cell proliferation and improving insulin resistance. It may have important clinical application prospects in aging related metabol-ic and cognitive degeneration. This article reviews the current research status of oxymatrine in pharmacokinetics,toxicology and pharmacology.
引文
[1]王素军,王广基,李晓天,等.氧化苦参碱在犬体内的药动学[J].中国医院药学杂志,2005,25(7):585-7.[1] Wang S J,Wang G J,Li X T,et al. Pharmacokinetics of oxymatrine in dogs[J]. Chin Hosp Pharm J,2005,25(7):585-7.
[2]王毅,郑文艳,刘栓娣.氧化苦参碱注射液的人体药代动力学[J].中国临床药理学杂志,2003,19(4):301-2.[2] Wang Y,Zheng W Y,Liu S D. Pharmacokinetics of oxymatrine injection in human body[J]. Chin J Clin Pharmacol,2003,19(4):301-2.
[3]栗志文,马小亚,王美纳,等.苦参素软胶囊的人体药代动力学研究[J].西北药学杂志,2004,19(4):149-51.[3] Li Z W,Ma X Y,Wang M N,et al. Study on pharmacokinetics of matrine soft capsules in human body[J]. Northwest Pharm J,2004,19(4):149-51.
[4]刘苏,秦晶,陆伟根,等.氧化苦参碱在大鼠体内药代动力学特征[J].中成药,2011,33(6):962-5.[4] Liu S,Qin J,Lu W G,et al. Pharmacokinetics of oxymatrine in rats[J]. Chin Tradit Patent Med,2011,33(6):962-5.
[5] Tang L,Dong L N,Peng X J,et al. Pharmacokinetic characterization of oxymatrine and matrine in rats after oral administration of radix sophorae tonkinensis extract and oxymatrine by sensitive and robust UPLC-MS/MS method[J]. J Pharmaceut Biomed,2013,83:179-85.
[6]谢明智,周文正,张瑛.氧化苦参碱的代谢[J].药学学报,1981,16(7):481-6.[6] Xie M Z,Zhou W Z,Zhang Y. Metabolism of oxymatrine[J]. Acta Pharm Sin,1981,16(7):481-6.
[7]王明雷,周秋丽,王本祥.氧化苦参碱肠内菌代谢及吸收入血活性成分的研究[J].中国中药杂志,2001,26(4):272-4.[7] Wang M L,Zhou Q L,Wang B X. Study on metabolism and absorption of active components of oxymatrine enterobacte[J]. China J Chin Mater Med,2001,26(4):272-4.
[8]刘继平,黄鑫,薛梅,等.复方苦参注射液大鼠胆汁,尿液排泄研究[J].中药新药与临床药理,2011,22(4):424-8.[8] Liu J P,Huang X,Xue M,et al. Study on bile and urine excretion in compound kushen injection in rats[J]. Tradit Chin Drug Res Pharmacol,2011,22(4):424-8.
[9]郭秋平,金若敏.苦参碱和氧化苦参碱致小鼠肝毒性比较[J].中国药理学与毒理学杂志,2016,30(7):736-40.[9] Guo Q P,Jin R M. Comparison of hepatotoxicity induced by matrine and oxymatrine in mice[J]. Chin J Pharmacol Toxicol,2016,30(7):736-40.
[10] Wen J B,Zhu F Q,Chen W G,et al. Oxymatrine improves intestinal epithelial barrier function involving NF-κB-mediated signaling pathway in CCl4-induced cirrhotic rats[J]. PLoS One,2014,9(8):e106082.
[11] Li L,Liu Q,Fan L,et al. Protective effects of oxymatrine against arsenic trioxide-induced liver injury[J]. Oncotarget,2017,8(8):12792-9.
[12] Ozturk H,Cetinkaya A,Yilmaz F. Protective effect of oxymatrine against renal ischemia/reperfusion injury in rats[J]. Bratisl Med J,2017,118(4):217-22.
[13] Jiang H,Meng F,Li J,et al. Anti-apoptosis effects of oxymatrine protect the liver from warm ischemia reperfusion injury in rats[J].World J Surg,2005,29(11):1397-401.
[14] Zhang X,Jiang W, Zhou A L, et al. Inhibitory effect of oxymatrine on hepatocyte apoptosis via TLR4/PI3K/Akt/GSK-3βsignaling pathway[J]. World J Gastroentero,2017,23(21):3839-49.
[15] Dong X Q,Yu W H,Hu Y Y,et al. Oxymatrine reduces neuronal cell apoptosis by inhibiting toll-like receptor 4/nuclear factor kappa-B-dependent inflammatory responses in traumatic rat brain injury[J]. Inflamm Res,2011,60(6):533-9.
[16] Mao J,Hu Y,Zhou A,et al. Oxymatrine reduces neuroinflammation in rat brain:a signaling pathway[J]. Neural Regen Res,2012,7(30):2333-9.
[17] Wang S,Jia J. Oxymatrine attenuates diabetes-associated cognitive deficits in rats[J]. Acta Pharmacol Sin,2014,35(3):331-8.
[18]蔡艳,蒋伟,周爱玲,等.苦参素通过p38/JNK信号途径对海马神经元凋亡的影响[J].中国中药杂志,2017,42(4):731-8.
[18] Cai Y,Jiang W,Zhou A L,et al. Effect of matrine on apoptosis of hippocampal neurons through p38/JNK signaling pathway[J].China J Chin Mat Med,2017,42(4):731-8.
[19]程钢,秦媛媛,程迪,等.氧化苦参碱对大鼠局灶性脑缺血损伤的保护作用及其抑制凋亡的作用机制[J].中国药理学通报,2013,29(3):387-92.[19] Cheng G,Qin Y Y,Cheng D, et al. Protective effect of oxymatrine on focal cerebral ischemia in rats and the mechanism of inhibiting apoptosis[J]. Chin Pharmacol Bull,2013,29(3):387-92.
[20] Li M,Zhang X,Cui L,et al. The neuroprotection of oxymatrine in cerebral ischemia/reperfusion is related to nuclear factor erythroid2-related factor 2(Nrf2)-mediated antioxidant response:role of Nrf2 and hemeoxygenase-1 expression[J]. Biol Pharm Bull,2011,34(5):595-601.
[21] Ge X H,Shao L,Zhu G J. Oxymatrine attenuates brain hypoxicischemic injury from apoptosis and oxidative stress:role of p-Akt/GSK3β/HO-1/Nrf-2 signaling pathway[J]. Metab Brain Dis,2018,33(6):1869-75.
[22] Dong X Q,Du Q,Yu W H,et al. Anti-inflammatory effects of oxymatrine through inhibition of nuclear factor-kappa Band mitogen-activated protein kinase activation in lipopolysaccharide-induced BV2 microglia cells[J]. Iran J Pharm Research,2013,12(1):165-74.
[23]张燕,李玲,王俊燕,等.氧化苦参碱对活化的小胶质细胞的抑制作用[J].教育教学论坛,2017,18:279-80.[23] Zhang Y,Li L,Wang J Y,et al. Inhibitory effect of oxymatrine on activated microglia cells[J]. Education Teaching Forum,2017,18:279-80.[24]余小虎,朱金水,顾国妹,等.氧化苦参碱联合二甲双胍对非酒精性脂肪肝患者胰岛素抵抗及血清TNF-α的影响[J].临床肝胆病杂志,2007,23(3):195-6.[24] Yu X H,Zhu J S,Gu G M,et al. Clinical effects of oxymatrine combined with metformin on insulin resistance and serum TNF-αin patients with non-alcoholic fatty liver[J]. J Clin Hepatol,2007,23(3):195-6.
[25] Guo C,Zhang C,Li L,et al. Hypoglycemic and hypolipidemic effects of oxymatrine in high-fat diet and streptozotocin-induced diabetic rats[J]. Phytomedicine,2014,21(6):807-14.
[26]王杏,王超,宋光耀,等.氧化苦参碱对高脂诱导胰岛素抵抗ApoE-/-小鼠肝脏脂代谢相关基因的影响[J].中国药理学通报,2015,31(12):1688-92.[26] Wang X,Wang C,Song G Y,et al. Effect of oxymatrine on lipid metabolism related genes in liver of Apo E-/-mice induced by hyperlipidemia[J]. Chin Pharmacol Bull,2015,31(12):1688-92.
[27]王超,张会欣,邢邯英,等.氧化苦参碱抑制p38 MAPK通路减轻高脂喂养胰岛素抵抗小鼠氧化应激[J].中国中药杂志,2016,41(15):2872-6.[27] Wang C,Zhang H X,Xing H Y,et al. Inhibitory effect of oxymatrine on p38 MAPK pathway to alleviate oxidative stress in high-fat fed insulin resistant mice[J]. China J Chin Mater Med,2016,41(15):2872-6.
[28]王超,张会欣,邢邯英,等.氧化苦参碱对胰岛素抵抗小鼠肝脂质转运酶的作用[J].中国临床药理学杂志,2017,33(11):996-9.[28] Wang C,Zhang H X,Xing H Y,et al. Effect of oxymatrine on liver lipid transporter in insulin resistance mice[J]. Chin J Clin Pharmacol,2017,33(11):996-9.
[29]吴琴,高云.氧化苦参碱药理作用的分子机制研究进展[J].中国药理学通报,2015,31(6):759-62.[29] Wu Q,Gao Y. Progress in molecular mechanism of pharmacological action of oxymatrine[J]. Chin Pharmacol Bull,2015,31(6):759-62.
[30] Wu J,Cai Y,Li M,et al. Oxymatrine promotes S-phase arrest and inhibits cell proliferation of human breast cancer cells in vitro through mitochondria-mediated apoptosis[J]. Biol Pharm Bull,2017,40(8):1232-9.
[2]王毅,郑文艳,刘栓娣.氧化苦参碱注射液的人体药代动力学[J].中国临床药理学杂志,2003,19(4):301-2.[2] Wang Y,Zheng W Y,Liu S D. Pharmacokinetics of oxymatrine injection in human body[J]. Chin J Clin Pharmacol,2003,19(4):301-2.
[3]栗志文,马小亚,王美纳,等.苦参素软胶囊的人体药代动力学研究[J].西北药学杂志,2004,19(4):149-51.[3] Li Z W,Ma X Y,Wang M N,et al. Study on pharmacokinetics of matrine soft capsules in human body[J]. Northwest Pharm J,2004,19(4):149-51.
[4]刘苏,秦晶,陆伟根,等.氧化苦参碱在大鼠体内药代动力学特征[J].中成药,2011,33(6):962-5.[4] Liu S,Qin J,Lu W G,et al. Pharmacokinetics of oxymatrine in rats[J]. Chin Tradit Patent Med,2011,33(6):962-5.
[5] Tang L,Dong L N,Peng X J,et al. Pharmacokinetic characterization of oxymatrine and matrine in rats after oral administration of radix sophorae tonkinensis extract and oxymatrine by sensitive and robust UPLC-MS/MS method[J]. J Pharmaceut Biomed,2013,83:179-85.
[6]谢明智,周文正,张瑛.氧化苦参碱的代谢[J].药学学报,1981,16(7):481-6.[6] Xie M Z,Zhou W Z,Zhang Y. Metabolism of oxymatrine[J]. Acta Pharm Sin,1981,16(7):481-6.
[7]王明雷,周秋丽,王本祥.氧化苦参碱肠内菌代谢及吸收入血活性成分的研究[J].中国中药杂志,2001,26(4):272-4.[7] Wang M L,Zhou Q L,Wang B X. Study on metabolism and absorption of active components of oxymatrine enterobacte[J]. China J Chin Mater Med,2001,26(4):272-4.
[8]刘继平,黄鑫,薛梅,等.复方苦参注射液大鼠胆汁,尿液排泄研究[J].中药新药与临床药理,2011,22(4):424-8.[8] Liu J P,Huang X,Xue M,et al. Study on bile and urine excretion in compound kushen injection in rats[J]. Tradit Chin Drug Res Pharmacol,2011,22(4):424-8.
[9]郭秋平,金若敏.苦参碱和氧化苦参碱致小鼠肝毒性比较[J].中国药理学与毒理学杂志,2016,30(7):736-40.[9] Guo Q P,Jin R M. Comparison of hepatotoxicity induced by matrine and oxymatrine in mice[J]. Chin J Pharmacol Toxicol,2016,30(7):736-40.
[10] Wen J B,Zhu F Q,Chen W G,et al. Oxymatrine improves intestinal epithelial barrier function involving NF-κB-mediated signaling pathway in CCl4-induced cirrhotic rats[J]. PLoS One,2014,9(8):e106082.
[11] Li L,Liu Q,Fan L,et al. Protective effects of oxymatrine against arsenic trioxide-induced liver injury[J]. Oncotarget,2017,8(8):12792-9.
[12] Ozturk H,Cetinkaya A,Yilmaz F. Protective effect of oxymatrine against renal ischemia/reperfusion injury in rats[J]. Bratisl Med J,2017,118(4):217-22.
[13] Jiang H,Meng F,Li J,et al. Anti-apoptosis effects of oxymatrine protect the liver from warm ischemia reperfusion injury in rats[J].World J Surg,2005,29(11):1397-401.
[14] Zhang X,Jiang W, Zhou A L, et al. Inhibitory effect of oxymatrine on hepatocyte apoptosis via TLR4/PI3K/Akt/GSK-3βsignaling pathway[J]. World J Gastroentero,2017,23(21):3839-49.
[15] Dong X Q,Yu W H,Hu Y Y,et al. Oxymatrine reduces neuronal cell apoptosis by inhibiting toll-like receptor 4/nuclear factor kappa-B-dependent inflammatory responses in traumatic rat brain injury[J]. Inflamm Res,2011,60(6):533-9.
[16] Mao J,Hu Y,Zhou A,et al. Oxymatrine reduces neuroinflammation in rat brain:a signaling pathway[J]. Neural Regen Res,2012,7(30):2333-9.
[17] Wang S,Jia J. Oxymatrine attenuates diabetes-associated cognitive deficits in rats[J]. Acta Pharmacol Sin,2014,35(3):331-8.
[18]蔡艳,蒋伟,周爱玲,等.苦参素通过p38/JNK信号途径对海马神经元凋亡的影响[J].中国中药杂志,2017,42(4):731-8.
[18] Cai Y,Jiang W,Zhou A L,et al. Effect of matrine on apoptosis of hippocampal neurons through p38/JNK signaling pathway[J].China J Chin Mat Med,2017,42(4):731-8.
[19]程钢,秦媛媛,程迪,等.氧化苦参碱对大鼠局灶性脑缺血损伤的保护作用及其抑制凋亡的作用机制[J].中国药理学通报,2013,29(3):387-92.[19] Cheng G,Qin Y Y,Cheng D, et al. Protective effect of oxymatrine on focal cerebral ischemia in rats and the mechanism of inhibiting apoptosis[J]. Chin Pharmacol Bull,2013,29(3):387-92.
[20] Li M,Zhang X,Cui L,et al. The neuroprotection of oxymatrine in cerebral ischemia/reperfusion is related to nuclear factor erythroid2-related factor 2(Nrf2)-mediated antioxidant response:role of Nrf2 and hemeoxygenase-1 expression[J]. Biol Pharm Bull,2011,34(5):595-601.
[21] Ge X H,Shao L,Zhu G J. Oxymatrine attenuates brain hypoxicischemic injury from apoptosis and oxidative stress:role of p-Akt/GSK3β/HO-1/Nrf-2 signaling pathway[J]. Metab Brain Dis,2018,33(6):1869-75.
[22] Dong X Q,Du Q,Yu W H,et al. Anti-inflammatory effects of oxymatrine through inhibition of nuclear factor-kappa Band mitogen-activated protein kinase activation in lipopolysaccharide-induced BV2 microglia cells[J]. Iran J Pharm Research,2013,12(1):165-74.
[23]张燕,李玲,王俊燕,等.氧化苦参碱对活化的小胶质细胞的抑制作用[J].教育教学论坛,2017,18:279-80.[23] Zhang Y,Li L,Wang J Y,et al. Inhibitory effect of oxymatrine on activated microglia cells[J]. Education Teaching Forum,2017,18:279-80.[24]余小虎,朱金水,顾国妹,等.氧化苦参碱联合二甲双胍对非酒精性脂肪肝患者胰岛素抵抗及血清TNF-α的影响[J].临床肝胆病杂志,2007,23(3):195-6.[24] Yu X H,Zhu J S,Gu G M,et al. Clinical effects of oxymatrine combined with metformin on insulin resistance and serum TNF-αin patients with non-alcoholic fatty liver[J]. J Clin Hepatol,2007,23(3):195-6.
[25] Guo C,Zhang C,Li L,et al. Hypoglycemic and hypolipidemic effects of oxymatrine in high-fat diet and streptozotocin-induced diabetic rats[J]. Phytomedicine,2014,21(6):807-14.
[26]王杏,王超,宋光耀,等.氧化苦参碱对高脂诱导胰岛素抵抗ApoE-/-小鼠肝脏脂代谢相关基因的影响[J].中国药理学通报,2015,31(12):1688-92.[26] Wang X,Wang C,Song G Y,et al. Effect of oxymatrine on lipid metabolism related genes in liver of Apo E-/-mice induced by hyperlipidemia[J]. Chin Pharmacol Bull,2015,31(12):1688-92.
[27]王超,张会欣,邢邯英,等.氧化苦参碱抑制p38 MAPK通路减轻高脂喂养胰岛素抵抗小鼠氧化应激[J].中国中药杂志,2016,41(15):2872-6.[27] Wang C,Zhang H X,Xing H Y,et al. Inhibitory effect of oxymatrine on p38 MAPK pathway to alleviate oxidative stress in high-fat fed insulin resistant mice[J]. China J Chin Mater Med,2016,41(15):2872-6.
[28]王超,张会欣,邢邯英,等.氧化苦参碱对胰岛素抵抗小鼠肝脂质转运酶的作用[J].中国临床药理学杂志,2017,33(11):996-9.[28] Wang C,Zhang H X,Xing H Y,et al. Effect of oxymatrine on liver lipid transporter in insulin resistance mice[J]. Chin J Clin Pharmacol,2017,33(11):996-9.
[29]吴琴,高云.氧化苦参碱药理作用的分子机制研究进展[J].中国药理学通报,2015,31(6):759-62.[29] Wu Q,Gao Y. Progress in molecular mechanism of pharmacological action of oxymatrine[J]. Chin Pharmacol Bull,2015,31(6):759-62.
[30] Wu J,Cai Y,Li M,et al. Oxymatrine promotes S-phase arrest and inhibits cell proliferation of human breast cancer cells in vitro through mitochondria-mediated apoptosis[J]. Biol Pharm Bull,2017,40(8):1232-9.