中药甘草的药代动力学以及药物相互作用研究进展

摘要/Abstract

摘要： 甘草是最古老和最常用的中草药之一,药理作用多样且临床应用广泛,但甘草也会引起不良反应和药物相互作用,了解甘草的化学成分、体内处置以及潜在的药物相互作用,对于它的临床安全、合理使用具有重要意义。本文综述并讨论了近几十年来关于甘草的药代动力学以及药物相互作用研究,促进对甘草的全面认识,保证临床用药安全。

关键词: 甘草, 化学成分, 药代动力学, 药物相互作用

Abstract: Licorice is one of the oldest and most frequently employed botanicals in Chinese medicine with multiple pharmacological effects, and a wide range of clinical application. But licorice can also cause adverse effects and drug interactions. A clear understanding of the chemical composition, disposition and drug interactions of licorice is contributed to promote its usage rationally and safely in clinic. In this paper, pharmacokinetics and drug interactions of licorice are reviewed and discussed in recent several decades, in order to get a more comprehensive understanding about licorice and ensure the safety of clinical medication.

Key words: Licorice, Chemical component, Pharmacokinetics, Drug interaction

中图分类号:

R969

陈江飞, 徐萍, 朱素燕, 胡毅坚. 中药甘草的药代动力学以及药物相互作用研究进展[J]. 中国临床药理学与治疗学, 2010, 15(10): 1174-1182.

CHEN Jiang-fei, XU Ping, ZHU Su-yan, HU Yi-jian. Advance in research for pharmacokinetics and drug interactions of licorice[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2010, 15(10): 1174-1182.

参考文献

[1] Afreen F,Zobayed SMA,Kozai T.Spectral quality and UV-B stress stimulate glycyrrhizin concentration of Glycyrrhiza uralensis in hydroponic and pot system[J].Plant Physiol Biochem,2005,43(12):1074-1081.
[2] 田代华.实用中药辞典(上卷)[M].北京:人民卫生出版社,2002:428-429.
[3] 朱绪民,邸迎彤,彭树林,等.乌拉尔甘草中的化学成分[J].中草药,2003,34(3):199-201.
[4] Li JR,Wang YQ,Deng ZZ.Two new compounds from glycyrrhiza glabra[J].J Asian Nat Prod Res,2005,7(4):677-680.
[5] 吴汉夔,赵芸,牟新利,等.新疆甘草化学成分研究[J].天然产物研究与开发,2006,18(3):415-417.
[6] Kinoshita T,Tamura Y,Mizutani K.The isolation and structure elucidation of minor isoflavonoids from licorice of glycyrrhiza glabra origin[J].Chem Pharm Bull,2005,53(7):847-849.
[7] Hatano T,Aga Y,Shintani Y,et al.Minor flavonoids from licorice[J].Phytochemistry,2000,55(8):959-963.
[8] 白虹,窦德强,裴玉萍,等.栽培甘草的化学成分研究[J].中草药,2005,36(5):652-654.
[9] Cantelli-Forti G,Maffei F,Hrelia P,et al.Interaction of licorice on glycyrrhizin pharmacokinetics[J].Environ Health Perspect,1994,102(9):65-68.
[10] Wang Z,Kurosaki Y,Nakayama T,et al.Mechanism of gastrointestinal absorption of glycyrrhizin in rats[J].Biol Pharm Bull,1994,17(10):1399-1403.
[11] Yamamura Y,Santa T,Kotaki H,et al.Administration-route dependency of absorption of glycyrrhizin in rats: intraperitoneal administration dramatically enhanced bioavailability[J].Biol Pharm Bull,1995,18(2):337-341.
[12] Gunnarsdottir S,Johannesson T.Glycyrrhetic acid in human blood after ingestion of glycyrrhizic acid in licorice[J].Pharmacol Toxicol,1997,81(6):300-302.
[13] Takeda S,Ishihara K,Wakui Y,et al.Bioavailability study of glycyrrhetic acid after oral administration of glycyrrhizin in rats; relevance to the intestinal bacterial hydrolysis[J].J Pharm Pharmacol,1996,48(9):902-905.
[14] Gunnarsdottir S,Johannesson T.Glycyrrhetic acid in human blood after ingestion of glycyrrhizic acid in licorice[J].Pharmacol Toxicol,1997,81(6):300-302.
[15] Hou YC,Hsiu SL,Ching H,et al.Profound difference of metabolic pharmacokinetics between pure glycyrrhizin and glycyrrhizin in licorice decoction[J].Life Sci,2005,76(10):1167-1176.
[16] Wang Z,Nishioka M,Kurosaki Y,et al.Gastrointestinal absorption characteristics of glycyrrhizin from glycyrrhiza extract[J].Biol Pharm Bull,1995,18(9):1238-1241.
[17] Cantelli-Forti G,Raggi MA,Bugamelli F,et al.Toxicological assessment of liquorice: biliary excretion in rats[J].Pharmacol Res,1997,35(5):463-470.
[18] 任平,黄熙,张莉,等.脾虚证大鼠甘草甜素药物动力学特征与胃肠动力的关系研究[J].安徽中医学院学报,2000,19(4):47-50.
[19] 任平,黄熙,张莉,等.不同脾虚时期大鼠甘草甜素药物动力学特征及其机制的探讨[J].成都中医药大学学报,2000,23(2):30-32.
[20] Akao T.Localization of enzymes involved in metabolism of glycyrrhizin in contents of rat gastrointestinal tract[J].Biol Pharm Bull,1997,20(2):122-126.
[21] Akao T.Hydrolysis of glycyrrhetyl mono-glucuronide to glycyrrhetic acid by glycyrrhetyl mono-glucuronide β-D-glucuronidase of Eubacterium sp. GLH[J].Biol Pharm Bull,1997,20(12):1245-1249.
[22] Kim DH,Lee SW,Han MJ.Biotransformation of glycyrrhizin to 18β-glycyrrhetinic acid-3-O-β-D -glucuronide by Streptococcus LJ-22, a human intestinal bacterium[J].Biol Pharm Bull,1999,22(3):320-322.
[23] Kim DH,Hong SW,Kim BT,et al.Biotransformation of glycyrrhizin by human intestinal bacteria and its relation to biological activities[J].Arch Pharm Res,2000,23(2):172-173.
[24] Kato H,Kanaoka M,Yano S,et al.3-Monoglucuronyl-glycyrrhetinic acids is a major metabolite that causes licorice-induced pseudoaldosteronism[J]. J Clin Endocrinol Metab,1995,80(6):1929-1933.
[25] Mizuhara Y,Takizawa Y,Ishihara K,et al.The influence of the sennosides on absorption of glycyrrhetic acid in rats[J].Biol Pharm Bull,2005,28(10):1897-1902.
[26] Ching H,Hou YC,Hsiu SL,et al.Influence of honey on the gastrointestinal metabolism and disposition of glycyrrhizin and glycyrrhetic acid in rabbits[J].Biol Pharm Bull,2002,25(1):87-91.
[27] Ishida S,Ichikawa T,Sakiya Y.Binding of glycyrrhetinic acid to rat plasma, rat serum albumin, human serum, and human serum albumin[J].Chem Pharm Bull,1988,36(1):440-443.
[28] Ishida S,Sakiya Y,Ichikawa T,et al.Binding of glycyrrhizin to human serum and human serum albumin[J].Chem Pharm Bull,1989,37(1):226-228.
[29] Koga K,Tomoyama M,Ohyanagi K,et al.Pharmacokinetics of glycyrrhizin in normal and albumin-deficient rats[J].Biopharm Drug Dispos,2008,29(7):373-381.
[30] Ishida S,Sakiya Y,Ichikawa T,et al.Pharmacokinetics of glycyrrhetic acid, a major metabolite of glycyrrhizin, in rats[J].Chem Pharm Bull,1989,37(9):2509-2413.
[31] Ichikawa T,Ishida S,Sakiya Y,et al.High-performance liquid chromatographic determination of glycyrrhizin and glycyrrhetinic acid in biological materials[J].Chem Pharm Bull,1984,32(9):3734-3738.
[32] 范益,丁建花,刘苏怡,等.α-与β-甘草酸在小鼠体内分布的研究[J].中国临床药理学与治疗学,2004,9(6):619-622.
[33] Hundertmark S,Dill A,Buhler H,et al.11β-Hydroxysteroid dehydrogenase type 1: a new regulator of fetal lung maturation[J].Horm Metab Res,2002,34(10):537-544.
[34] Ishida S,Sakiya Y,Ichikawa T,et al.Dose-dependent pharmacokinetics of glycyrrhizin in rats[J].Chem Pharm Bull,1992,40(7):1917-1920.
[35] Ishida S,Sakiya Y,Ichikawa T,et al.Uptake of glycyrrhizin by isolated rat hepatocytes[J].Biol Pharm Bull,1993,16(3):293-297.
[36] Ishida S,Sakiya Y,Taira Z.Disposition of glycyrrhizin in the perfused liver of rats[J].Biol Pharm Bull,1994,17(7):960-969.
[37] Kawakami J,Yamamura Y,Santa T,et al.Kinetic analysis of glycyrrhetic acid, an active metabolite of glycyrrhizin, in rats: role of enterohepatic circulation[J].J Pharm Sci,1993,82(3):301-305.
[38] Iveson P,Lindup WE,Parke DV,et al.The metabolism of carbenoxolone in the rat[J].Xenobiotica,1971,1(1):79-95.
[39] Akao T,Aoyama M,Akao T,et al.Metabolism of glycyrrhetic acid by rat liver microsomes Ⅱ 22α- and 24-hydroxylation[J].Biochem Pharmacol,1990,40(2):291-296.
[40] 高凯,余伟,杨静,等.大鼠肝微粒体CYP3A1/2和CYP2C9/10参与甘草次酸的羟化代谢[J].中国临床药理学与治疗学,2007,12(11):1255-1260.
[41] Akao T,Akao T,Kobashi K.Metabolism of glycyrrhetic acid by rat liver microsomes: glycyrrhetinate dehydrogenase[J].Biochim Biophys Acta,1990,1042(2):241-246.
[42] Akao T,Akao T,Aoyama M,et al.Metabolism of glycyrrhetic acid by rat liver microsomes-Ⅲ. Male-specific glycyrrhetinate dehydrogenase[J].Biochem Pharmacol,1991,42(1):103-107.
[43] Jing J,Ren W,Chen X,et al.Glucuronide-sulfate diconjugate as a novel metabolite of glycyrrhetic acid in rat bile[J].Drug Metab Pharmacokinet,2008,23(3):175-180.
[44] Yamamura Y,Kawakami J,Santa T,et al.Pharmacokinetic profile of glycyrrhizin in healthy volunteers by a new high-performance liquid chromatographic method[J].J Pharma Sci,1992,81(10):1042-1046.
[45] van Rossum TG,Vulto AG,Hop WC,et al.Pharmacokinetics of intravenous glycyrrhizin after single and multiple doses in patients with chronic hepatitis C infection[J].Clin Ther,1999,21(12):2080-2090.
[46] Yamamura Y,Tanaka N,Santa T,et al.The relationship between pharmacokinetic behaviour of glycyrrhizin and hepatic function in patients with acute hepatitis and liver cirrhosis[J].Biopharm Drug Dispos,1995,16(1):13-21.
[47] Krahenbuhl S,Hasler F,Frey BM,et al.Kinetics and dynamics of orally administered 18β-glycyrrhetinic acid in humans[J].J Clin Endocrinol Metab,1994,78(3):581-585.
[48] Ploeger B,Mensinga T,Sips A,et al.A human physiologically-based model for glycyrrhzic acid, a compound subject to presystemic metabolism and enterohepatic cycling[J].Pharm Res,2000,17(12):1516-1525.
[49] Kamei J,Saitoh A,Asano T,et al.Pharmacokinetic and pharmacodynamic profiles of the antitussive principles of glycyrrhizae radix(licorice), a main component of the Kampo preparation Bakumondo-to(Mai-men-dong-tang)[J].Eur J Pharmacol,2005,507(1/3):163-168.
[50] Aoki F,Nakagawa K,Kitano M,et al.Clinical safety of licorice flavonoid oil(LFO) and pharmacokinetics of glabridin in healthy humans[J].J American College of Nutrition,2007,26(3):209-218.
[51] Paolini M,Pozzetti L,Sapone A,et al.Effect of licorice and glycyrrhizin on murine liver CYP-dependent monooxygenases[J].Life Sci,1998,62(6):571-582.
[52] Paolini M,Barillari J,Broccoli M,et al.Effect of liquorice and glycyrrhizin on rat liver carcinogen metabolizing enzymes[J].Cancer Lett,1999,145(1/2):35-42.
[53] Hu WY,Li YW,Hou YN,et al.The induction of liver microsomal cytochrome P450 by glycyrrhiza uralensis and glycyrrhetinic acid in mice[J].Biomed Environ Sci,1999,12(1):10-14.
[54] 张锦楠,李亚伟,徐艳霞,等.甘草和五味子对大鼠肝微粒体CYP450诱导作用的研究[J].中国药学杂志,2002,37(6):424-426.
[55] 徐艳霞,张锦楠,闫淑莲.甘草和五味子对大鼠丙咪嗪药代动力学的影响[J].首都医科大学学报,2003,24(2):121-123.
[56] Tang J,Song X,Zhu M,et al.Study on the pharmacokinetics drug-drug interaction potential of glycyrrhiza uralensis, a traditional Chinese medicine, with lidocaine in rats[J].Phytother Res,2009,23(5):603-607.
[57] Mu Y,Zhang JN,Zhang SM,et al.Traditional Chinese medicines Wu Wei Zi(Schisandra chinensis Bail) and Gan Cao(Glycyrrhiza uralensis Fisch) activate pregnane X receptor and increase warfarin clearance in rats[J].J Pharmacol Exp Ther,2006,316(3):1369-1377.
[58] 贺平,吴孟超,李琳芳,等.甘草酸对小鼠安替比林及醋氨酚代谢的影响[J].中国药理学通报,1998,14(6):516-519.
[59] 徐君辉,李士敏.甘草提取液与甘草酸对小鼠安替比林代谢影响的比较[J].中成药,2007,29(11):1673-1675.
[60] Tu JH,Hu DL,Dai LL,et al.Effect of glycyrrhizin on CYP2C19 and CYP3A4 activity in healthy volunteers with different CYP2C19 genotypes[J].Xenobiotica,2010,40(6):393-399.
[61] Budzinski JW,Foster BC,Vandenhoek S,et al.An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures [J].2000,Phytomedicine,7(4):273-282.
[62] Kent UM,Aviram M,Rosenbalt M,et al.The licorice root derived isoflavin glabridin inhibits the activities of human cytochrome P450S 3A4, 2B6 and 2C9 [J].Drug Metab Dispos,2002,30(6):709-715.
[63] Tsukamoto S,Aburatani M,Yoshida T,et al.CYP3A4 inhibitors isolated from licorice [J].Biol Pharm Bull,2005,28(10):2000-2002.
[64] 王宇光,杨明今,马增春,等.18β-甘草酸和18α-甘草酸对大鼠原代肝细胞CYP3A酶表达的影响[J].中国中药杂志,2009,34(3):307-311.
[65] 杨静,彭仁琇,孔锐,等.18α-甘草酸二铵对大鼠肝脏细胞色素P450和Ⅱ相酶的影响[J].药学学报,2001,36(5):321-324.
[66] 陈洁,彭仁琇.18α-甘草酸二铵对格列本脲在实验性糖尿病大鼠体内药动学的影响[J].中国药学杂志,2006,41(10):774-776.
[67] Chen MF,Shimada F,Kato H,et al.Effect of oral administration of glycyrrhizin on the pharmacokinetics of prednisolone[Abstract].Endocrinol Jpn,1991,38(2):167-174.
[68] Homma M,Oka K,Ikeshima K,et al.Different effects of traditional Chinese medicines containing similar herbal constituents on prednisolone pharmacokinetics[J].J Pharm Pharmacol,1995,47(8):687-692.
[69] Chen L,Yang J,Davey AK,et al.Effects of diammonium glycyrrhizinate on the pharmacokinetics of aconitine in rats and the potential mechanism[J].Xenobiotica,2009,39(12):955-963.
[70] Lin SP,Tsai SY,Hou YC,et al.Glycyrrhizin and licorice significantly affect the pharmacokinetics of methotrexate in rats[J].J Agric Food Chem,2009,57(5):1854-1859.
[71] 程建峰,滕树保,陈东鸿,等.甘草酸和苯巴比妥钠对小鼠肝P450 3A酶的影响[J].第四军医大学学报,2000,21(8):968-970.