痹祺胶囊组方配伍对细胞色素P450同工酶活性的影响
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摘要
研究目的:痹祺胶囊是应用现代药物制剂理论精制而成的新药,主要用于风湿、类风湿性关节炎,颈椎病、肩周炎等疾病的治疗。具有疗效好、见效快、止痛作用好的特点。目前对于痹祺胶囊组方配伍的科学性及用药安全性尚未见报道。本实验是国家自然科学基金委重点项目(No. 30630075)的重要组成部分,通过体外实验及体内实验两方面全面评价痹祺胶囊配伍组方的基于细胞色素P450 (Cytochrome P450, CYP450)的安全性和科学性。
研究方法:采用液相色谱-串联质谱法(LC-MS/MS)建立同时评价CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A酶活性的全新高通量分析方法,同时提取并检测5种特异性探针药物及其相应代谢产物,其中包括非那西丁/扑热息痛、甲苯磺丁脲/4-羟基甲苯磺丁脲/羧基甲苯磺丁脲、4’-羟基美芬妥英、右美沙芬/右啡烷、咪达唑仑/1’-羟基咪达唑仑。采用Gentest高通量重组CYP450酶抑制剂筛选试剂盒分别考察痹祺全药提取物、君药有效成分马钱子碱和士的宁及其与使药甘草的有效成分甘草酸和甘草次酸相结合对以上5种CYP450的体外抑制作用。采用“Cocktail”一点法测定痹祺胶囊配伍组分对Wistar大鼠体内5种CYP450的诱导和(或)抑制作用,并全面分析配伍规律。
结果:本实验建立了全新“Cocktail”探针药物组合(非那西丁+甲苯磺丁脲+美芬妥英+右美沙芬+咪达唑仑),并建立了同时检测以上五种探针药物及其相应代谢产物的LC-MS/MS分析方法。马钱子碱和士的宁对5种CYP450基本没有体外抑制作用。马钱子碱和士的宁分别加上甘草酸和甘草次酸后对CYP2C9和CYP2C19可能存在体外抑制作用。大鼠体内实验结果显示,痹祺胶囊组方存在基于CYP450的配伍规律,与空白对照组比较,君药+臣药组、君药+使药组、君药+臣药+佐药组、君药+臣药+使药组、君药+佐药+使药组及痹祺胶囊全药组对CYP1A2具有显著诱导作用;君药+臣药组、君药+臣药+佐药组、君药+臣药+使药组及痹祺胶囊全药组对CYP2C9具有显著诱导作用。
结论:本实验所建立的“Cocktail”探针药物组合为首次将此五种探针药物进行组合的全新方法,之前未见报道。痹祺胶囊组方存在基于CYP450较为显著的配伍规律,此规律为进一步探讨君药、臣药、佐药和使药在痹祺胶囊组方中的配伍作用地位,全面综合地分析与评价痹祺胶囊组方配伍的科学性奠定良好基础。
Biqi capsulae is a new drug made and refined according to morden pharmaceutical preparation theory. It is for the treatment of rheumatic arthritis, rhermatoid arthritis, cervical spondylopathy, scapulohumeral periarthritis and so on. Biqi capsulae has the advantages of good and rapid healing efficacy and excellent pain relieveing effect. There is no report on the scientificalness and safety of prescription compatibility of Biqi capsulae. This study is an important part of Key Program of National Natural Science Foundation of China (No. 30630075). This study is aimed to investigate and evaluate the scientificalness and safety of Biqi capsulae prescription compatibility on cytochrome P450 (CYP450).
A new high-throughput LC-MS/MS method was established to evaluate the in vivo activities of CYP1A2, 2C9, 2C19, 2D6 and 3A in rat plasma and urine. The five-specific probe substrates / metabolites include phenacetin / paracetamol (CYP1A2), tolbutamide / 4-hydroxytolbutamide / carboxytolbutamide (CYP2C9), mephenytoin / 4’-hydroxymephenytoin (CYP2C19), dextromethorphan / dextrorphan (CYP2D6) and midazolam / 1’-hydroxymidazolam (CYP3A). Using High-throughput Inhibitor Screening Kit, we determined the in vitro inhibitory effects of Biqi capsulae extract, active constituents of semen strychni (brucine and strychnine), brucine and strychnine combined with active constituents of Glycyrrhiza uralensis (glycyrrhetic acid and glycyrrhetinic acid) on the above 5 CYPs. Wistar rats were used to analyze and test the potential in vivo induction and (or) inhibition of constituents from Biqi prescription on the above 5 CYPs.
A new“Cocktail”has been established, including probes of phenacetin, tolbutamide, mephenytoin, dextromephen and midazolam. A LC-MS/MS analytical method has been established to determine the above 5 probes and their corresponding metabolites. The results showed that brucine and strychnine had no in vitro inhibitory effect on 5 CYPs. It is possible that groups of brucine and strychnine combined with glycyrrhetic acid and glycyrrhetinic acid had in vitro inhibitory effects on CYP2C9 and CYP2C19. The in vivo results showed that Biqi capsulae prescription has compatibility on CYP450s. Compared with blank group, groups of“principal + assistant”,“principal + mediator”,“principal + assistant + complement”,“principal + assistant + mediator”,“principal + complement + mediator”and Biqi capsulae can significantly induce the activity of CYP1A2. Moreover, groups of“principal + assistant”,“principal + assistant + complement”,“principal + assistant + mediator”and Biqi capsulae can significantly induce the activity of CYP2C9.
Biqi capsulae prescription has significant compatibility on CYP450s. These results provide important information and establish good foundation for further investigation on scientificalness and safety of Biqi capsulae prescription compatibility.
研究方法:采用液相色谱-串联质谱法(LC-MS/MS)建立同时评价CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A酶活性的全新高通量分析方法,同时提取并检测5种特异性探针药物及其相应代谢产物,其中包括非那西丁/扑热息痛、甲苯磺丁脲/4-羟基甲苯磺丁脲/羧基甲苯磺丁脲、4’-羟基美芬妥英、右美沙芬/右啡烷、咪达唑仑/1’-羟基咪达唑仑。采用Gentest高通量重组CYP450酶抑制剂筛选试剂盒分别考察痹祺全药提取物、君药有效成分马钱子碱和士的宁及其与使药甘草的有效成分甘草酸和甘草次酸相结合对以上5种CYP450的体外抑制作用。采用“Cocktail”一点法测定痹祺胶囊配伍组分对Wistar大鼠体内5种CYP450的诱导和(或)抑制作用,并全面分析配伍规律。
结果:本实验建立了全新“Cocktail”探针药物组合(非那西丁+甲苯磺丁脲+美芬妥英+右美沙芬+咪达唑仑),并建立了同时检测以上五种探针药物及其相应代谢产物的LC-MS/MS分析方法。马钱子碱和士的宁对5种CYP450基本没有体外抑制作用。马钱子碱和士的宁分别加上甘草酸和甘草次酸后对CYP2C9和CYP2C19可能存在体外抑制作用。大鼠体内实验结果显示,痹祺胶囊组方存在基于CYP450的配伍规律,与空白对照组比较,君药+臣药组、君药+使药组、君药+臣药+佐药组、君药+臣药+使药组、君药+佐药+使药组及痹祺胶囊全药组对CYP1A2具有显著诱导作用;君药+臣药组、君药+臣药+佐药组、君药+臣药+使药组及痹祺胶囊全药组对CYP2C9具有显著诱导作用。
结论:本实验所建立的“Cocktail”探针药物组合为首次将此五种探针药物进行组合的全新方法,之前未见报道。痹祺胶囊组方存在基于CYP450较为显著的配伍规律,此规律为进一步探讨君药、臣药、佐药和使药在痹祺胶囊组方中的配伍作用地位,全面综合地分析与评价痹祺胶囊组方配伍的科学性奠定良好基础。
Biqi capsulae is a new drug made and refined according to morden pharmaceutical preparation theory. It is for the treatment of rheumatic arthritis, rhermatoid arthritis, cervical spondylopathy, scapulohumeral periarthritis and so on. Biqi capsulae has the advantages of good and rapid healing efficacy and excellent pain relieveing effect. There is no report on the scientificalness and safety of prescription compatibility of Biqi capsulae. This study is an important part of Key Program of National Natural Science Foundation of China (No. 30630075). This study is aimed to investigate and evaluate the scientificalness and safety of Biqi capsulae prescription compatibility on cytochrome P450 (CYP450).
A new high-throughput LC-MS/MS method was established to evaluate the in vivo activities of CYP1A2, 2C9, 2C19, 2D6 and 3A in rat plasma and urine. The five-specific probe substrates / metabolites include phenacetin / paracetamol (CYP1A2), tolbutamide / 4-hydroxytolbutamide / carboxytolbutamide (CYP2C9), mephenytoin / 4’-hydroxymephenytoin (CYP2C19), dextromethorphan / dextrorphan (CYP2D6) and midazolam / 1’-hydroxymidazolam (CYP3A). Using High-throughput Inhibitor Screening Kit, we determined the in vitro inhibitory effects of Biqi capsulae extract, active constituents of semen strychni (brucine and strychnine), brucine and strychnine combined with active constituents of Glycyrrhiza uralensis (glycyrrhetic acid and glycyrrhetinic acid) on the above 5 CYPs. Wistar rats were used to analyze and test the potential in vivo induction and (or) inhibition of constituents from Biqi prescription on the above 5 CYPs.
A new“Cocktail”has been established, including probes of phenacetin, tolbutamide, mephenytoin, dextromephen and midazolam. A LC-MS/MS analytical method has been established to determine the above 5 probes and their corresponding metabolites. The results showed that brucine and strychnine had no in vitro inhibitory effect on 5 CYPs. It is possible that groups of brucine and strychnine combined with glycyrrhetic acid and glycyrrhetinic acid had in vitro inhibitory effects on CYP2C9 and CYP2C19. The in vivo results showed that Biqi capsulae prescription has compatibility on CYP450s. Compared with blank group, groups of“principal + assistant”,“principal + mediator”,“principal + assistant + complement”,“principal + assistant + mediator”,“principal + complement + mediator”and Biqi capsulae can significantly induce the activity of CYP1A2. Moreover, groups of“principal + assistant”,“principal + assistant + complement”,“principal + assistant + mediator”and Biqi capsulae can significantly induce the activity of CYP2C9.
Biqi capsulae prescription has significant compatibility on CYP450s. These results provide important information and establish good foundation for further investigation on scientificalness and safety of Biqi capsulae prescription compatibility.
引文
[1]周权,姚彤炜,曾苏,药物代谢分型的研究进展,中国现代应用药物杂志,2000, 17 (6): 423~428
[2] Zhou HH, Zeen T, James F. Cocktail approaches and strategies in drug development: valuable tool or flawed science? J Clin Pharmacol, 2004, 44: 120~143
[3] Schellens JHM, Ghabrial H, van der Wart HHF, et al. Differential effects of quinidine on the disposition of nifedipine, sparteine, and mephenytoin in humans. Clin Pharmacol Ther, 1991, 50: 520~528
[4] Shelepova T, Nafziger AN, Victory J, et al. Effect of a triphasic oral contraceptive on drug metabolizing enzyme activity as measured by the validated cooperstown 5+1 cocktail. J Clin. Pharmacol, 2005, 45: 1413~1421
[5]扈金萍,闫淑莲,唐静成等,Cocktail探针药物评价姜黄对肝细胞色素P450酶的影响,首都医科大学学报,2004, 25 (4): 427~430
[6]闫淑萍,扈金萍,徐艳霞等,Cocktail探针药物同时评价连翘对肝细胞色素P450酶的影响,中国药学杂志,2003, 38 (10): 761~763
[7] Liu S, Frye RF, Branch RA, et al. Effect of age and postoperative time on cytochrome P450 enzyme activity following liver transplantation. J Clin Pharmacol, 2005, 45: 666~673
[8] May CB, Csuka ME, Lupoli S, et al. Activity of oxidative routes of metabolism of debrisoquin, mephenytoin, and dapsone is unrelated to the pathogenesis of vinyl chloride-induced disease. Clin Pharmacol Ther, 1992, 52: 659~667
[9] Branch RA, Chem HD, Adedoyin A, et al. The procarcinogen hypothesis for bladder cancer: activities of individual drug metabolizing enzymes as risk factors. Pharmcogenetics, 1995, 5: 97~102
[10] Tett SE, Kirkpatrick CM, Gross AS, et al. Principles and clinical application of assessing alternations in renel elimination pathways. Clin Pharmacokinet, 2003, 42: 1193~1211.
[11] Gross AS, Mclachlan AJ, Minns I, et al. Simultaneous administration of a cocktail of markers to measure renal drug elimination pathways: absence of a pharmacokinetic interaction between fluconazole and sinistrin, p-aminohippuric acidand pindolol. Br J Clin. Pharmacol, 2001, 51: 547~555
[12] Frye RF, Matzke GR, Adedoyin A, et al. Validation of the five-drug "Pittsburgh cocktail" approach for assessment of selective regulation of drug-metabolizing enzymes. Clin Pharmacol Ther, 1997, 62 (4): 365~376
[13] Damkier P, Brosen K, Quinidine as a probe for CYP3A4 activity: intrasubject variability and lack of correlation with probe-based assays for CYP1A2, CYP2C9, CYP2C19, and CYP2D6. Clin Pharmacol Ther, 2000, 68 (2): 199~209
[14] Scott RJ, Palmer J, Lewis IA, et al, Determination of a 'GW cocktail' of cytochrome P450 probe substrates and their metabolites in plasma and urine using automated solid phase extraction and fast gradient liquid chromatography tandem mass spectrometry. Rapid Commun Mass Spectrom, 1999, 13 (23): 2305~2319
[15] Palmer JL, Scott RJ, Gibson A, et al. An interaction between the cytochrome P450 probe substrates chlorzoxazone (CYP2E1) and midazolam (CYP3A). Br J Clin Pharmacol, 2001, 52 (5): 555~561
[16] Streetman DS, Bleakley JF, Kim JS, et al. Combined phenotypic assessment of CYP1A2, CYP2C19, CYP2D6, CYP3A, N-acetyltransferase-2, and xanthine oxidase with the "Cooperstown cocktail". Clin Pharmacol Ther, 2000, 68 (4): 375~383
[17] Chainuvati S, Nafziger AN, Leeder JS, et al. Combined phenotypic assessment of cytochrome P450 1A2, 2C9, 2C19, 2D6, and 3A, N-acetyltransferase-2, and xanthine oxidase activities with the "Cooperstown 5+1 cocktail". Clin Pharmacol Ther, 2003, 74 (5): 437~547
[18] Christensen M, Andersson K, Dalen P, et al. The Karolinska cocktail for phenotyping of five human cytochrome P450 enzymes. Clin Pharmacol Ther, 2003, 73 (6): 517~528
[19] Yin OQP, Lam SSL, Lo CMY, et al. Rapid determination of five probe drugs and their metabolites in human plasma and urine by liquid chromatography/tandem mass spectrometry: application to cytochrome P450 phenotyping studies. Rapid Commun Mass Spectrom, 2004, 18: 2921~2933
[20] Jerdi MC, Daali Y, Oestreicher MK, et al. A simplified analytical method for a phenotyping cocktail of major CYP450 biotransformation routes. J Pharm Biomed Anal, 2004, 35: 1203~1212
[21] Woolhouse NM, Eichelbaum M, Oates NS, et al. Dissociation of co-regulatory control of debrisoquin/phenformin and sparteine oxidation in Ghanaians.Clin Pharmacol Ther, 1985, 37: 512~521
[22] Droll K, Bruce-Mensah K, Otton SV, et al. Comparison of three CYP2D6 probe substrates and genotype in Ghanaians, Chinese and Caucasians. Pharmacogenetics, 1998, 8 (4): 325~333
[23] Tanaka E, Kurata N, Yasuhara H, How useful is the "cocktail approach" for evaluating human hepatic drug metabolizing capacity using cytochrome P450 phenotyping probes in vivo? J Clin Pharm Ther, 2003, 28 (3): 157~165
[24] Lee CR, Pieper JA, Frye RF, et al. Tolbutamide, flurbiprofen, and losartan as probes of CYP2C9 activity in humans. J Clin Pharmacol, 2003, 43 (1): 84~91
[25] Andersson T, Miners JO, Veronese ME, et al. Identification of human liver cytochrome P450 isoforms mediating omeprazole metabolism. Br J Clin Pharmacol, 1993, 36 (6): 521~530
[26] US Department of Health and Human Services Food and Drug Administration, Guidance for Industry: Bioanalytical Method Validation. US Department of Health and Human Services: Beltsville, MD, 2001
[27] Zhu B, Ou-Yang DS, Chen XP, et al. Assessment of cytochrome P450 activity by a five-drug cocktail approach.Clin Pharmacol Ther, 2001, 70 (5): 455~461
[28] Kashuba AD, Nafziger AN, Kearns GL, et al. Quantification of intraindividual variability and the influence of menstrual cycle phase on CYP2D6 activity as measured by dextromethorphan phenotyping. Pharmacogenetics, 1998, 8 (5): 403~410
[29] McCune JS, Lindley C, Decker JL, et al. Lack of gender differences and large intrasubject variability in cytochrome P450 activity measured by phenotyping with dextromethorphan. J Clin Pharmacol, 2001, 41 (7): 723~731
[30] Morin S, Loriot MA, Poirier JM, et al. Is diclofenac a valuable CYP2C9 probe in humans? Eur J Clin Pharmacol, 2001, 56 (11): 793~797
[31] Alvan G, Bechtel P, Iselius L, et al. Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol, 1990, 39 (6): 533~537
[32] Wilkinson GR, Guengerich FP, Branch RA, Genetic polymorphism of S-mephenytoin hydroxylation. Pharmacol Ther 1989, 43 (1): 53~76
[33] Xie HG, Xu ZH, Luo X, et al.Genetic polymorphisms of debrisoquine and S-mephenytoin oxidation metabolism in Chinese populations: a meta-analysis. Pharmacogenetics, 1996, 6 (3): 235~238
[34] Miners JO, Birkett DJ, The use of caffeine as a metabolic probe for human drug metabolizing enzymes. Gen Pharmacol, 1996, 27 (2): 245~249
[35] Welfare MR, Bassendine MF, Daly AK, The effect of NAT2 genotype and gender on the metabolism of caffeine in nonsmoking subjects. Br J Clin Pharmacol, 2000, 49 (3): 240~243
[36] Tantcheva-Poor I, Zaigler M, Rietbrock S, et al. Estimation of cytochrome P-450 CYP1A2 activity in 863 healthy Caucasians using a saliva-based caffeine test. Pharmacogenetics, 1999, 9 (2): 131~144
[37] Tolonen A, Petsalo A, Turpeinen M, et al. In vitro interaction cocktail assay for nine major cytochrome P450 enzymes with 13 probe reactions and a single LC/MSMS run: analytical validation and testing with monoclonal anti-CYP antibodies. J Mass Spectrom, 2007, 42 (7): 960~966
[38] Yao M, Zhu M, Sinz MW, et al. Development and full validation of six inhibition assays for five major cytochrome P450 enzymes in human liver microsomes using an automated 96-well microplate incubation format and LC-MS/MS analysis. J Pharm Biomed Anal, 2007, 44 (1): 211~223
[39] Yuan R, Madani S, Wei XX, et al. Evaluation of cytochrome P450 probe substrates commonly used by the pharmaceutical industry to study in vitro drug interactions. Drug Metab Dispos, 2002, 30 (12): 1311~1319
[40] Xiaodong S, Gatti G, Bartol A i, et al. Omeprazole does not enhance the metabolism of phenacetin, a marker of CYP1A2 activity, in healthy volunteers. Ther Drug Monit, 1994, 16 (3): 248~250
[41] Boobis AR, Lynch AM, Murray S, CYP1A2-catalyzed conversion of dietary heterocyclic amines to their proximate carcinogens is their major route of metabolism in humans. Cancer Res, 1994, 54 (1): 89~94
[42] Beresford AP, Ellis WJ, Avrton J, et al. Cytochrome P4501A (CYP1A) induction in rat and man by the benzodioxino derivative, fluparoxan. Xenobiotica, 1997, 27 (2): 159~173
[43] Frank D, Jaehde U, Fuhr U, Evaluation of probe drugs and pharmacokinetic metrics for CYP2D6 phenotyping. Eur J Clin Pharmacol, 2007, 63 (4): 321~333
[44]徐艳霞,中草药对肝细胞色素P450的作用,中国药理通讯,2005, 22 (3): 64
[45]朱立勤,娄建石,细胞色素P450与药物代谢的研究现状,中国临床药理学与治疗学,2004, 9 (10): 108l~1086
[46] Nelson DR. Cytochrome P450 and the individuality of species. Arch Biochem Biophys. 1999, 369 (1): 1~10
[47]张德昌,医学药理学,北京:北京医科大学中国协和医科大学联合出版社,l998, 96
[48]马嘶,药物代谢酶系,中国医院药学杂志,1985, 5 (4):162
[49]骆文香,张银娣,药物代谢中的肝细胞色素P450,药学进展,1999, 23 (1): 27~32
[50]戴军,陆伦根,曾民德等,肝细胞色素P450 2E1在实验性肝纤维化组织中的表达,肝脏,2000, 5 (1): 16~17
[51]金剑,肖忠革,陈慧瑾,细胞色素氧化酶CYP1A2基因多态性及其对代谢的影响,中国临床药物杂志,2005, 14(1): 60~62
[52] Daly AK, King BP. Pharmacogenetics of oral anticoagulants. Pharmacogenetics, 2003, 13 (5): 247~252
[53] Christensen IK, Hansen JM, Kristensen NM. Sulphaphen-nazoleinduced hypoglycaemic attacks in tolbutamide-treated diabetics. Lancet, 1963, 41: 1298~1301
[54] Selim K, Atila B, Lise B, et a1. CYP2C19 genotype does not represent a genetic predisposition in idiopathic systemic lupus erythematosus. Ann Rheum Dis, 1999, 5 (8): 182~185
[55]陈华芳,细胞色素氧化酶P4502C19的研究进展,中国肿瘤,2006, 15 (2): 116~119
[56] Kitada M. Genetic polymorphism of cytochrome P450 enzymes in Asian populations: focus on CYP2D6. Int J Clin Pharmacol Res, 2003, 23 (1): 31~35
[57]Charlier C, Broly F, Lhermitte M, et al. Polymorphisms in the CYP2D6 gene: association with plasma concentrations of fluoxetine and paroxetine. Ther Drug Monit, 2003, 25 (6): 738~742
[58] Staack RF, Patti LD, Springer D, et al. Cytochrome P450 dependent metabolism of the new designer drug 1-(3-trifluoromethylpheny1) piperazine (TFMPP). In vivo studies in Wistar and Dark Agouti rats as well as in vitro studies in human liver microsomes. Biochem Pharmacol, 2004, 67 (2): 235~244
[59] Rosenbrock H, Hagemeyer CE, Ditter M, et al. Identifieation, induction and loealization of eytochrome P450s 0f the 3A-subfamily in mouse brainl. Neurotox Res, 2001, 3 (4): 339~349
[60] Torimoto N, Ishii I, Hata M, et al. Direct interaction between substrates and endogenous steroids in the active site may change the aetivity of cytochrome 3A4.Biochemistry, 2003, 42 (51): 15068~15077
[61] Yamamoto T, Suzuki A, Kohno Y, High-throughput screening for the assessment of time-dependent inhibitions of new drug candidates on recombinant CYP2D6 and CYP3A4 using a single concentration method. Xenobiotica, 2004, 34 (1): 87~101
[62] Dilmaghanian S, Gerber JG, Filler SG, et al. Enantioselectivity of inhibition of eytochrome P450 3A4 by ketoconazole: Testosterone and methadone as substrates. Chirality, 2004, 16 (2): 79~85
[63] Ekins S, Ring BJ, Grace J, et al. Present and future in vitro approaches for drug metabolism. J Pharmacol Toxicol, 2000, 44 (1): 313~324
[64] Rodrigues AD. Drug-drug interactions. New York: Marcel Dekker Inc, 2002: 217~294
[65]林启寿,中草药成分化学,北京:科学出版社, 1977:779~780
[66]金丽容,甘草对马钱子的减毒作用研究,宁夏医学院学报,1996, 18 (1): 6~7
[67] He F, Bi HC, Xie ZY, et al. Rapid determination of six metabolites from multiple cytochrome P450 probe substrates in human liver microsome by liquid chromatography/mass spectrometry: application to high-throughput inhibition screening of terpenoids. Rapid Commun. Mass Spectrom, 2007, 21: 635~643
[68]陈红,刘杭,印晓青等,甘草酸的化学及生物活性,浙江中西医结合杂志,2007, 17 (2): 130~131
[69]陈建萍,吴伟康,张敏生等,中药复方配伍规律研究的思路与方法,中国实验方剂学杂志,2002, 6 (1): 1~4
[70]商洪才,张伯礼,高秀梅,方剂配伍研究探讨,中国中医药信息杂志,2002, 9 (7): 6~9
[71]刘昌孝,中药药代动力学研究的难点和热点,药学学报,2005, 40 (5): 395~401
[72]王睿,细胞色素P450氧化酶基因多态性对药物代谢影响的研究进展,中国临床药学杂志,2004, 20 (2): 134~138
[73]吴伯镛,细胞色素P450酶与合理用药,药品评价,2005, 2 (4): 301~302
[74]夏伟,细胞色素P450的研究进展,国外医学?卫生学分册,2000, 27 (7): 41~45
[75]Slaughter RL, Edwards DJ, Recent advances: The cytochrome P450 enzymes, Ann Pharmacother, 1995, 29 (6): 619~624
[76] Tian J, Kristopher W, Yang S, et al. Eight inhibitory monoclonal antibodies define the role of individual P450 in human liver microsomal diazepam, 7 Ethoxycoumarin, and imipramine metabolism. Drug Metab Dispos, 1999, 27 (1): 102~109
[77] Brosen K, Skjelbo E, Nielsen KK, Imipramine: a model drug for P450 research. Methods Enzymol, 1996, 272: 177~186
[78]马艳峰,高冬梅,通络散治疗类风湿性关节炎1196例临床研究,中国社区医师:综合版,2005, 7 (10): 55~56
[79]边新群,治疗类风湿性关节炎的中成药——痹祺胶囊,开卷有益—求医问药,2001, (12): 15
[80]刘维,周艳丽,张磊等,痹祺胶囊抗炎镇痛作用的实验研究,中国中医药科技,2006, 13 (5): 315~316
[81]边新群,刘维,痹祺胶囊治疗类风湿性关节炎的药效学实验研究,中华中医药杂志,2006, 21 (12): 773~774
[82]王景文,袁雪海,赵连根,痹祺胶囊对足肿胀及肢体血流作用的研究,中草药,1999, 30 (9): 686
[83]王琦玮,刘良,黄光照,马钱子的毒理学研究进展,法医学杂志,2004, 20 (3): 183~184
[84]赵珍东,黄兆胜,马钱子的毒副作用研究进展,国医论坛,2003,18 (1): 50~51
[85]李宝君,马钱子中毒致精神障碍1例,陕西中医,1995, 16 (7): 314
[86]赵红卫,翁世艾,朱燕娜等,马钱子碱对小鼠淋巴细胞功能的影响,中国药理学通报,1999, 15 (4): 354~356
[87]韩进军,马钱子中毒致急性肾功能衰竭死亡1例,中日友好医院学报,1999, 1 (3): 14
[88] Ueng YF, Kuo YH, Wang SY, et al. Induction of CYP1A by a diterpene quinone tanshinoneⅡA isolated from a medicinal herb Salvia miltiorrhiza in C57BL/6J but not in DBA/2J mice. Life Sci, 2004, 74: 885~896
[89] Kuo YH, Lin YL, Don MJ, et al. Induction of cytochrome P450-dependent monooxygenase by extracts of the medicinal herb Salvia miltiorrhiza. J Pharm Pharmacol, 2006, 58 (4): 521~7
[90] Yang XF, Wang NP, Lu WH, et al. Effects of Ginkgo biloba extract and tanshinone on cytochrome P-450 isozymes and glutathione transferase in rats. Acta Pharmacol Sin, 2003, 24(10): 1033~1038
[91]杨秋慧,孟宪清,复方丹参诱导人体P450 1A2作用观察,哈尔滨医科大学学报,1997, 31 (4): 295~296
[92] Hu WY, Li YW, Hou YN, The induction of liver microsomal cytochrome P450 by Glycyrrhiza uralensis and glycyrrhetinic acid in mice. Biomed Environ Sci, 1999, 12 (1): 10~14
[93]闫静,朱海光,刘志强等,马钱子与甘草配伍前后生物碱成分的变化规律,分析化学研究简报,2007, 35 (8): 1218~1220
[94]段韵,姜燕,符芸等,中药马钱子中毒死亡检验方法的研究,中国药学杂志,2006, 41 (21): 1616~1618
[95]李晓天,张丽容,王天奎等,马钱子碱在小鼠体内的组织分布马钱子碱在小鼠体内的组织分布,中国临床药理学与治疗学,2006, 11 (3): 342~344
[96]胡成穆,李俊,非甾体抗炎药药物代谢酶多态性的研究进展,安徽医药,2002, 6 (2): 3~6
[97]赵树进,袁进,CYP2C9基因多态性的分子学机制、基因型检测及对药物代谢的影响,广东医学,2006, 27 (8): 1268~1270
[98] Tang JC, Zhang JN, Wu YT, et al. Effect of the water extract and ethanol extract from traditional Chinese medicines Angelica sinensis (Oliv.) Diels, Ligusticum chuanxiong Hort. and Rheum palmatum L. on rat liver cytochrome P450 activity. Phytother Res, 2006, 20: 1046~1051
[99] Tsukamoto S, Aburatani M, Yoshida T, et al. CYP3A4 inhibitors isolated from Licorice. Biol Pharm Bull, 2005, 28 (10):2000~2002
[100]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,药学学报,2001, 36 (5): 321~324
[2] Zhou HH, Zeen T, James F. Cocktail approaches and strategies in drug development: valuable tool or flawed science? J Clin Pharmacol, 2004, 44: 120~143
[3] Schellens JHM, Ghabrial H, van der Wart HHF, et al. Differential effects of quinidine on the disposition of nifedipine, sparteine, and mephenytoin in humans. Clin Pharmacol Ther, 1991, 50: 520~528
[4] Shelepova T, Nafziger AN, Victory J, et al. Effect of a triphasic oral contraceptive on drug metabolizing enzyme activity as measured by the validated cooperstown 5+1 cocktail. J Clin. Pharmacol, 2005, 45: 1413~1421
[5]扈金萍,闫淑莲,唐静成等,Cocktail探针药物评价姜黄对肝细胞色素P450酶的影响,首都医科大学学报,2004, 25 (4): 427~430
[6]闫淑萍,扈金萍,徐艳霞等,Cocktail探针药物同时评价连翘对肝细胞色素P450酶的影响,中国药学杂志,2003, 38 (10): 761~763
[7] Liu S, Frye RF, Branch RA, et al. Effect of age and postoperative time on cytochrome P450 enzyme activity following liver transplantation. J Clin Pharmacol, 2005, 45: 666~673
[8] May CB, Csuka ME, Lupoli S, et al. Activity of oxidative routes of metabolism of debrisoquin, mephenytoin, and dapsone is unrelated to the pathogenesis of vinyl chloride-induced disease. Clin Pharmacol Ther, 1992, 52: 659~667
[9] Branch RA, Chem HD, Adedoyin A, et al. The procarcinogen hypothesis for bladder cancer: activities of individual drug metabolizing enzymes as risk factors. Pharmcogenetics, 1995, 5: 97~102
[10] Tett SE, Kirkpatrick CM, Gross AS, et al. Principles and clinical application of assessing alternations in renel elimination pathways. Clin Pharmacokinet, 2003, 42: 1193~1211.
[11] Gross AS, Mclachlan AJ, Minns I, et al. Simultaneous administration of a cocktail of markers to measure renal drug elimination pathways: absence of a pharmacokinetic interaction between fluconazole and sinistrin, p-aminohippuric acidand pindolol. Br J Clin. Pharmacol, 2001, 51: 547~555
[12] Frye RF, Matzke GR, Adedoyin A, et al. Validation of the five-drug "Pittsburgh cocktail" approach for assessment of selective regulation of drug-metabolizing enzymes. Clin Pharmacol Ther, 1997, 62 (4): 365~376
[13] Damkier P, Brosen K, Quinidine as a probe for CYP3A4 activity: intrasubject variability and lack of correlation with probe-based assays for CYP1A2, CYP2C9, CYP2C19, and CYP2D6. Clin Pharmacol Ther, 2000, 68 (2): 199~209
[14] Scott RJ, Palmer J, Lewis IA, et al, Determination of a 'GW cocktail' of cytochrome P450 probe substrates and their metabolites in plasma and urine using automated solid phase extraction and fast gradient liquid chromatography tandem mass spectrometry. Rapid Commun Mass Spectrom, 1999, 13 (23): 2305~2319
[15] Palmer JL, Scott RJ, Gibson A, et al. An interaction between the cytochrome P450 probe substrates chlorzoxazone (CYP2E1) and midazolam (CYP3A). Br J Clin Pharmacol, 2001, 52 (5): 555~561
[16] Streetman DS, Bleakley JF, Kim JS, et al. Combined phenotypic assessment of CYP1A2, CYP2C19, CYP2D6, CYP3A, N-acetyltransferase-2, and xanthine oxidase with the "Cooperstown cocktail". Clin Pharmacol Ther, 2000, 68 (4): 375~383
[17] Chainuvati S, Nafziger AN, Leeder JS, et al. Combined phenotypic assessment of cytochrome P450 1A2, 2C9, 2C19, 2D6, and 3A, N-acetyltransferase-2, and xanthine oxidase activities with the "Cooperstown 5+1 cocktail". Clin Pharmacol Ther, 2003, 74 (5): 437~547
[18] Christensen M, Andersson K, Dalen P, et al. The Karolinska cocktail for phenotyping of five human cytochrome P450 enzymes. Clin Pharmacol Ther, 2003, 73 (6): 517~528
[19] Yin OQP, Lam SSL, Lo CMY, et al. Rapid determination of five probe drugs and their metabolites in human plasma and urine by liquid chromatography/tandem mass spectrometry: application to cytochrome P450 phenotyping studies. Rapid Commun Mass Spectrom, 2004, 18: 2921~2933
[20] Jerdi MC, Daali Y, Oestreicher MK, et al. A simplified analytical method for a phenotyping cocktail of major CYP450 biotransformation routes. J Pharm Biomed Anal, 2004, 35: 1203~1212
[21] Woolhouse NM, Eichelbaum M, Oates NS, et al. Dissociation of co-regulatory control of debrisoquin/phenformin and sparteine oxidation in Ghanaians.Clin Pharmacol Ther, 1985, 37: 512~521
[22] Droll K, Bruce-Mensah K, Otton SV, et al. Comparison of three CYP2D6 probe substrates and genotype in Ghanaians, Chinese and Caucasians. Pharmacogenetics, 1998, 8 (4): 325~333
[23] Tanaka E, Kurata N, Yasuhara H, How useful is the "cocktail approach" for evaluating human hepatic drug metabolizing capacity using cytochrome P450 phenotyping probes in vivo? J Clin Pharm Ther, 2003, 28 (3): 157~165
[24] Lee CR, Pieper JA, Frye RF, et al. Tolbutamide, flurbiprofen, and losartan as probes of CYP2C9 activity in humans. J Clin Pharmacol, 2003, 43 (1): 84~91
[25] Andersson T, Miners JO, Veronese ME, et al. Identification of human liver cytochrome P450 isoforms mediating omeprazole metabolism. Br J Clin Pharmacol, 1993, 36 (6): 521~530
[26] US Department of Health and Human Services Food and Drug Administration, Guidance for Industry: Bioanalytical Method Validation. US Department of Health and Human Services: Beltsville, MD, 2001
[27] Zhu B, Ou-Yang DS, Chen XP, et al. Assessment of cytochrome P450 activity by a five-drug cocktail approach.Clin Pharmacol Ther, 2001, 70 (5): 455~461
[28] Kashuba AD, Nafziger AN, Kearns GL, et al. Quantification of intraindividual variability and the influence of menstrual cycle phase on CYP2D6 activity as measured by dextromethorphan phenotyping. Pharmacogenetics, 1998, 8 (5): 403~410
[29] McCune JS, Lindley C, Decker JL, et al. Lack of gender differences and large intrasubject variability in cytochrome P450 activity measured by phenotyping with dextromethorphan. J Clin Pharmacol, 2001, 41 (7): 723~731
[30] Morin S, Loriot MA, Poirier JM, et al. Is diclofenac a valuable CYP2C9 probe in humans? Eur J Clin Pharmacol, 2001, 56 (11): 793~797
[31] Alvan G, Bechtel P, Iselius L, et al. Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol, 1990, 39 (6): 533~537
[32] Wilkinson GR, Guengerich FP, Branch RA, Genetic polymorphism of S-mephenytoin hydroxylation. Pharmacol Ther 1989, 43 (1): 53~76
[33] Xie HG, Xu ZH, Luo X, et al.Genetic polymorphisms of debrisoquine and S-mephenytoin oxidation metabolism in Chinese populations: a meta-analysis. Pharmacogenetics, 1996, 6 (3): 235~238
[34] Miners JO, Birkett DJ, The use of caffeine as a metabolic probe for human drug metabolizing enzymes. Gen Pharmacol, 1996, 27 (2): 245~249
[35] Welfare MR, Bassendine MF, Daly AK, The effect of NAT2 genotype and gender on the metabolism of caffeine in nonsmoking subjects. Br J Clin Pharmacol, 2000, 49 (3): 240~243
[36] Tantcheva-Poor I, Zaigler M, Rietbrock S, et al. Estimation of cytochrome P-450 CYP1A2 activity in 863 healthy Caucasians using a saliva-based caffeine test. Pharmacogenetics, 1999, 9 (2): 131~144
[37] Tolonen A, Petsalo A, Turpeinen M, et al. In vitro interaction cocktail assay for nine major cytochrome P450 enzymes with 13 probe reactions and a single LC/MSMS run: analytical validation and testing with monoclonal anti-CYP antibodies. J Mass Spectrom, 2007, 42 (7): 960~966
[38] Yao M, Zhu M, Sinz MW, et al. Development and full validation of six inhibition assays for five major cytochrome P450 enzymes in human liver microsomes using an automated 96-well microplate incubation format and LC-MS/MS analysis. J Pharm Biomed Anal, 2007, 44 (1): 211~223
[39] Yuan R, Madani S, Wei XX, et al. Evaluation of cytochrome P450 probe substrates commonly used by the pharmaceutical industry to study in vitro drug interactions. Drug Metab Dispos, 2002, 30 (12): 1311~1319
[40] Xiaodong S, Gatti G, Bartol A i, et al. Omeprazole does not enhance the metabolism of phenacetin, a marker of CYP1A2 activity, in healthy volunteers. Ther Drug Monit, 1994, 16 (3): 248~250
[41] Boobis AR, Lynch AM, Murray S, CYP1A2-catalyzed conversion of dietary heterocyclic amines to their proximate carcinogens is their major route of metabolism in humans. Cancer Res, 1994, 54 (1): 89~94
[42] Beresford AP, Ellis WJ, Avrton J, et al. Cytochrome P4501A (CYP1A) induction in rat and man by the benzodioxino derivative, fluparoxan. Xenobiotica, 1997, 27 (2): 159~173
[43] Frank D, Jaehde U, Fuhr U, Evaluation of probe drugs and pharmacokinetic metrics for CYP2D6 phenotyping. Eur J Clin Pharmacol, 2007, 63 (4): 321~333
[44]徐艳霞,中草药对肝细胞色素P450的作用,中国药理通讯,2005, 22 (3): 64
[45]朱立勤,娄建石,细胞色素P450与药物代谢的研究现状,中国临床药理学与治疗学,2004, 9 (10): 108l~1086
[46] Nelson DR. Cytochrome P450 and the individuality of species. Arch Biochem Biophys. 1999, 369 (1): 1~10
[47]张德昌,医学药理学,北京:北京医科大学中国协和医科大学联合出版社,l998, 96
[48]马嘶,药物代谢酶系,中国医院药学杂志,1985, 5 (4):162
[49]骆文香,张银娣,药物代谢中的肝细胞色素P450,药学进展,1999, 23 (1): 27~32
[50]戴军,陆伦根,曾民德等,肝细胞色素P450 2E1在实验性肝纤维化组织中的表达,肝脏,2000, 5 (1): 16~17
[51]金剑,肖忠革,陈慧瑾,细胞色素氧化酶CYP1A2基因多态性及其对代谢的影响,中国临床药物杂志,2005, 14(1): 60~62
[52] Daly AK, King BP. Pharmacogenetics of oral anticoagulants. Pharmacogenetics, 2003, 13 (5): 247~252
[53] Christensen IK, Hansen JM, Kristensen NM. Sulphaphen-nazoleinduced hypoglycaemic attacks in tolbutamide-treated diabetics. Lancet, 1963, 41: 1298~1301
[54] Selim K, Atila B, Lise B, et a1. CYP2C19 genotype does not represent a genetic predisposition in idiopathic systemic lupus erythematosus. Ann Rheum Dis, 1999, 5 (8): 182~185
[55]陈华芳,细胞色素氧化酶P4502C19的研究进展,中国肿瘤,2006, 15 (2): 116~119
[56] Kitada M. Genetic polymorphism of cytochrome P450 enzymes in Asian populations: focus on CYP2D6. Int J Clin Pharmacol Res, 2003, 23 (1): 31~35
[57]Charlier C, Broly F, Lhermitte M, et al. Polymorphisms in the CYP2D6 gene: association with plasma concentrations of fluoxetine and paroxetine. Ther Drug Monit, 2003, 25 (6): 738~742
[58] Staack RF, Patti LD, Springer D, et al. Cytochrome P450 dependent metabolism of the new designer drug 1-(3-trifluoromethylpheny1) piperazine (TFMPP). In vivo studies in Wistar and Dark Agouti rats as well as in vitro studies in human liver microsomes. Biochem Pharmacol, 2004, 67 (2): 235~244
[59] Rosenbrock H, Hagemeyer CE, Ditter M, et al. Identifieation, induction and loealization of eytochrome P450s 0f the 3A-subfamily in mouse brainl. Neurotox Res, 2001, 3 (4): 339~349
[60] Torimoto N, Ishii I, Hata M, et al. Direct interaction between substrates and endogenous steroids in the active site may change the aetivity of cytochrome 3A4.Biochemistry, 2003, 42 (51): 15068~15077
[61] Yamamoto T, Suzuki A, Kohno Y, High-throughput screening for the assessment of time-dependent inhibitions of new drug candidates on recombinant CYP2D6 and CYP3A4 using a single concentration method. Xenobiotica, 2004, 34 (1): 87~101
[62] Dilmaghanian S, Gerber JG, Filler SG, et al. Enantioselectivity of inhibition of eytochrome P450 3A4 by ketoconazole: Testosterone and methadone as substrates. Chirality, 2004, 16 (2): 79~85
[63] Ekins S, Ring BJ, Grace J, et al. Present and future in vitro approaches for drug metabolism. J Pharmacol Toxicol, 2000, 44 (1): 313~324
[64] Rodrigues AD. Drug-drug interactions. New York: Marcel Dekker Inc, 2002: 217~294
[65]林启寿,中草药成分化学,北京:科学出版社, 1977:779~780
[66]金丽容,甘草对马钱子的减毒作用研究,宁夏医学院学报,1996, 18 (1): 6~7
[67] He F, Bi HC, Xie ZY, et al. Rapid determination of six metabolites from multiple cytochrome P450 probe substrates in human liver microsome by liquid chromatography/mass spectrometry: application to high-throughput inhibition screening of terpenoids. Rapid Commun. Mass Spectrom, 2007, 21: 635~643
[68]陈红,刘杭,印晓青等,甘草酸的化学及生物活性,浙江中西医结合杂志,2007, 17 (2): 130~131
[69]陈建萍,吴伟康,张敏生等,中药复方配伍规律研究的思路与方法,中国实验方剂学杂志,2002, 6 (1): 1~4
[70]商洪才,张伯礼,高秀梅,方剂配伍研究探讨,中国中医药信息杂志,2002, 9 (7): 6~9
[71]刘昌孝,中药药代动力学研究的难点和热点,药学学报,2005, 40 (5): 395~401
[72]王睿,细胞色素P450氧化酶基因多态性对药物代谢影响的研究进展,中国临床药学杂志,2004, 20 (2): 134~138
[73]吴伯镛,细胞色素P450酶与合理用药,药品评价,2005, 2 (4): 301~302
[74]夏伟,细胞色素P450的研究进展,国外医学?卫生学分册,2000, 27 (7): 41~45
[75]Slaughter RL, Edwards DJ, Recent advances: The cytochrome P450 enzymes, Ann Pharmacother, 1995, 29 (6): 619~624
[76] Tian J, Kristopher W, Yang S, et al. Eight inhibitory monoclonal antibodies define the role of individual P450 in human liver microsomal diazepam, 7 Ethoxycoumarin, and imipramine metabolism. Drug Metab Dispos, 1999, 27 (1): 102~109
[77] Brosen K, Skjelbo E, Nielsen KK, Imipramine: a model drug for P450 research. Methods Enzymol, 1996, 272: 177~186
[78]马艳峰,高冬梅,通络散治疗类风湿性关节炎1196例临床研究,中国社区医师:综合版,2005, 7 (10): 55~56
[79]边新群,治疗类风湿性关节炎的中成药——痹祺胶囊,开卷有益—求医问药,2001, (12): 15
[80]刘维,周艳丽,张磊等,痹祺胶囊抗炎镇痛作用的实验研究,中国中医药科技,2006, 13 (5): 315~316
[81]边新群,刘维,痹祺胶囊治疗类风湿性关节炎的药效学实验研究,中华中医药杂志,2006, 21 (12): 773~774
[82]王景文,袁雪海,赵连根,痹祺胶囊对足肿胀及肢体血流作用的研究,中草药,1999, 30 (9): 686
[83]王琦玮,刘良,黄光照,马钱子的毒理学研究进展,法医学杂志,2004, 20 (3): 183~184
[84]赵珍东,黄兆胜,马钱子的毒副作用研究进展,国医论坛,2003,18 (1): 50~51
[85]李宝君,马钱子中毒致精神障碍1例,陕西中医,1995, 16 (7): 314
[86]赵红卫,翁世艾,朱燕娜等,马钱子碱对小鼠淋巴细胞功能的影响,中国药理学通报,1999, 15 (4): 354~356
[87]韩进军,马钱子中毒致急性肾功能衰竭死亡1例,中日友好医院学报,1999, 1 (3): 14
[88] Ueng YF, Kuo YH, Wang SY, et al. Induction of CYP1A by a diterpene quinone tanshinoneⅡA isolated from a medicinal herb Salvia miltiorrhiza in C57BL/6J but not in DBA/2J mice. Life Sci, 2004, 74: 885~896
[89] Kuo YH, Lin YL, Don MJ, et al. Induction of cytochrome P450-dependent monooxygenase by extracts of the medicinal herb Salvia miltiorrhiza. J Pharm Pharmacol, 2006, 58 (4): 521~7
[90] Yang XF, Wang NP, Lu WH, et al. Effects of Ginkgo biloba extract and tanshinone on cytochrome P-450 isozymes and glutathione transferase in rats. Acta Pharmacol Sin, 2003, 24(10): 1033~1038
[91]杨秋慧,孟宪清,复方丹参诱导人体P450 1A2作用观察,哈尔滨医科大学学报,1997, 31 (4): 295~296
[92] Hu WY, Li YW, Hou YN, The induction of liver microsomal cytochrome P450 by Glycyrrhiza uralensis and glycyrrhetinic acid in mice. Biomed Environ Sci, 1999, 12 (1): 10~14
[93]闫静,朱海光,刘志强等,马钱子与甘草配伍前后生物碱成分的变化规律,分析化学研究简报,2007, 35 (8): 1218~1220
[94]段韵,姜燕,符芸等,中药马钱子中毒死亡检验方法的研究,中国药学杂志,2006, 41 (21): 1616~1618
[95]李晓天,张丽容,王天奎等,马钱子碱在小鼠体内的组织分布马钱子碱在小鼠体内的组织分布,中国临床药理学与治疗学,2006, 11 (3): 342~344
[96]胡成穆,李俊,非甾体抗炎药药物代谢酶多态性的研究进展,安徽医药,2002, 6 (2): 3~6
[97]赵树进,袁进,CYP2C9基因多态性的分子学机制、基因型检测及对药物代谢的影响,广东医学,2006, 27 (8): 1268~1270
[98] Tang JC, Zhang JN, Wu YT, et al. Effect of the water extract and ethanol extract from traditional Chinese medicines Angelica sinensis (Oliv.) Diels, Ligusticum chuanxiong Hort. and Rheum palmatum L. on rat liver cytochrome P450 activity. Phytother Res, 2006, 20: 1046~1051
[99] Tsukamoto S, Aburatani M, Yoshida T, et al. CYP3A4 inhibitors isolated from Licorice. Biol Pharm Bull, 2005, 28 (10):2000~2002
[100]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,药学学报,2001, 36 (5): 321~324