甘草酸对CYP450酶的影响及其机制研究
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摘要
背景：细胞色素P450酶系在人体内参与许多内源性和外源性物质的生物转化。药物对细胞色素P450酶活性的影响,是导致药物相互作用的主要原因之一。甘草及甘草酸制剂的应用日益增长,和其它临床药物合用的可能性增加。现有的研究表明甘草及甘草酸对动物体内CYP450酶的影响,但是尚无甘草及甘草酸对人体内CYP450酶的作用的研究报道。有研究证实甘草水溶性提取物可以激动人及动物PXR,因此对由PXR调控的代谢酶必然会产生影响,此外由于CYP450酶的种系差异的存在,因此探明甘草及甘草酸对人体内CYP450酶的影响,避免由P450酶影响而介导的药物相互作用是必要而具重要意义的。
目的：检测甘草的主要成分甘草酸对人体内CYP3A、CYP1A2、CYP2E1、CYP2D6活性的影响。
方法：应用COCKTAIL方法及单点法在人体内初步筛查甘草酸对人体内CYP3A、CYP1A2、CYP2E1、CYP2D6活性的影响。征集12名健康男性志愿者,加入双周期交叉实验,每周期受试者接受甘草酸或安慰剂处理14天,第15天同时服用探药咪达唑仑、咖啡因、氯唑沙宗和美托洛尔,采集单点外周静脉血及收集尿样来检测各时间点相应的药物及相应代谢产物的浓度。
结果：服用甘草酸两周使1小时血浆中1-羟基咪达唑仑和咪达唑仑的比值显著升高(p=0.021),但是却显著降低6小时17X/137X的浓度之比(p=0.004)以及4小时6-羟基氯唑沙宗／氯唑沙宗的比值(p=0.021)；甘草酸处理对0-8小时尿样中美托洛尔与α-羟基美托洛尔浓度的比值没有影响(p=0.248),
结论：口服甘草酸14天能够诱导体内CYP3A酶活性；对CYP1A2、CYP2E1酶活性有抑制作用。甘草酸的服用对CYP2D6酶活性没有明显影响。
背景：甘草及甘草酸的应用日益广泛,尤其现代用于慢性肝炎的治疗,剂量增加及疗程延长,其与其他药物合用的机会增加,但是其对人体内CYP450酶的影响却未见报道。我们第一部分用鸡尾酒法和单点法研究显示甘草酸能够诱导CYP3A酶,但是由于单点法的限制,甘草酸对CYP3A的诱导程度以及对咪达唑仑的药代动力学参数的影响和可能发生的临床药物相互作用还是未知的。
目的：应用CYP3A最经典探药咪达唑仑进一步探讨甘草酸对人体内CYP3A酶活性的影响,并观察甘草酸对咪达唑仑药代动力学的影响及其可能的甘草酸与咪达唑仑的药物相互作用。
方法：征集16名健康男性志愿者,加入双周期交叉实验,每周期受试者接受甘草酸或安慰剂处理14天,第15天同时服用探药咪达唑仑7.5mg,收集O-12小时血样,LC-MS/MS方法检测血浆中咪达唑仑及其代谢产物1-羟基咪达唑仑的药物浓度。
结果：服用甘草酸两周使咪达唑仑Cmax显著降低12%(p<0.01；95%CI：-28.86 to 4.03)；相应的咪达唑仑AUC0-∞显著降低by 20.2%(p<0.05；95%CI：-31.76 to-8.66)。而1-羟基咪达唑仑Cmax明显升高19.1%(p<0.01；95%CI：10.6 to27.7)；1-羟基咪达唑仑AUC0-∞显著增加20.3%(p<0.01；95%CI：11.0 to 29.6)。对咪达唑仑的药代动力学参数AUC0-∞和Cmax进行生物等效性分析,其90%可信区间均超出0.8-1.25的生物等效范围.
结论：长期(14天)的甘草酸的服用诱导体内CYP3A酶活性,使体内咪达唑仑的药代动力学参数发生变化,生物等效性分析超出等效范围具有临床意义。
背景：传统中药甘草的主要成分有甘草酸、甘草次酸、甘草黄酮、多羟基酚等成分。水溶性提取物中甘草酸是主要成分,有少量甘草次酸。但甘草酸口服后主要经肠道酶作用水解转化为甘草次酸吸收入血。我们前面临床实验证实口服甘草酸能够诱导体内CYP3A活性,抑制CYP1A2及CYP2E1活性,而对CYP2D6活性无影响,为了探讨其作用机制,我们首先拟在肝微粒体水平探讨甘草酸及其水解产物甘草次酸对CYP450酶的直接作用效应。
目的：研究甘草酸及甘草次酸对人肝微粒体中CYP 1 A2、CYP3A4、CYP2C19、CYP2E1、CYP2D6酶活性的影响。
方法：用体外实验人肝微粒体孵化体系的方法,分别以咖啡因、咪哒唑仑、奥美拉唑、氯唑沙宗、美托洛尔为探针药,利用HPLC方法测定探针药与相应代谢产物的浓度,以代谢产物的产率为酶活性指标,评估甘草酸及甘草次酸在人肝微粒体孵化体系中对CYP1A2、CYP3A、CYP2C19、CYP3A4、CYP2D6、CYP2E1酶活性的影响。为揭开甘草酸对人体内P450酶的作用机制提供有益信息。
结果：在人肝微粒体反应体系中,甘草酸(0-200μM)对CYP1A2、CYP3A4、CYP2C19、CYP2E1、CYP2D6酶活性均无明显影响。同时观察到甘草次酸自10μM浓度开始对CYP3A介导的l羟咪达唑仑的生成和CYP3A4介导的奥美拉唑磺化作用均有明显抑制效应,且随着甘草次酸浓度的升高,对酶的抑制作用加强,其IC50值分别是32.94±9.51、141.28±22.46μM。甘草次酸自25μM浓度开始抑制CYP2C19介导的奥美拉唑羟化作用,IC50值为176.35±22.46μM。酶促动力学分析,甘草次酸对CYP3A催化的咪达唑仑1’羟化作用的抑制类型为非竞争性抑制,抑制常数为7.38±0.93μM。
结论：甘草酸在肝微粒体水平,对CYP1A2、CYP3A、CYP2C19、CYP3A4、CYP2D6、CYP2E 1酶活性无明显影响。甘草次酸非竞争性抑制CYP3A介导的咪达唑仑1位羟化活性,对CYP3A4介导的奥美拉唑磺化和CYP2C19介导的羟化有明显的抑制作用。
背景：以往研究表明甘草能够提高啮齿动物肝脏中多种CYP450酶的活性,并且甘草水溶性提取物是人PXR激动剂。但是甘草中何种成分对CYP450酶产生影响及何种成分激动PXR及其分子机制都不清楚。与此相一致的,我们前面的体内实验表明口服甘草酸会引起人体内CYP3A酶活性的增加,而肝微粒体实验却表明甘草次酸非竞争性抑制CYP3A4酶。为进一步探讨其体内诱导机制,我们拟从核受体PXR、CAR的调控角度来分析,观察甘草酸或甘草次酸是否通过核受体影响CYP3A基因表达而使体内酶活性增加。肝微粒体实验观察到甘草次酸抑制CYP2C19酶活性,为了正确预测口服甘草酸对体内CYP2C19活性的影响,我们也观察甘草酸或甘草次酸是否通过核受体对CYP2C19的调控产生影响。
目的：观察甘草酸及甘草次酸是否通过孕烷核受体PXR或激活组成性核受体CAR途径,诱导细胞色素CYP3A4、CYP2C19的转录表达。
方法：在人肝肿瘤细胞株HepG2细胞和人结肠癌细胞株Caco2细胞中,用瞬时转染报告基因试验检测甘草酸及甘草次酸对核受体PXR或CAR介导的CYP3A4、CYP2C19的转录调节作用。同时应用Real-time PCR检验甘草次酸对高表达PXR/RXRa或CAR/RXRa的肠道上皮肿瘤细胞株中CYP3A4mRNA表达的影响,并应用LC-MS/MS方法检测甘草次酸引起的CYP3A4活性的变化。为揭开并预测甘草及甘草酸对人体内CYP3A4及CYP2C19的影响和作用机制提供有益信息。
结果：在瞬时转染的报告基因试验中,甘草酸不通过核受体PXR或CAR对CYP3A4或CYP2C19的转录表达产生影响。而甘草次酸在超高表达PXR和RXRa的肠道腺癌细胞株Caco2细胞中,能够引起CYP3A4的转录表达增加,而在超高表达PXR和RXRa的肝脏的肝癌细胞株HepG2细胞中,甘草次酸没有表现诱导CYP3A4转录表达的作用。无论在肝脏还是肠道肿瘤细胞株,甘草次酸均表现通过CAR诱导CYP3A4的转录表达。在同样的瞬时转染的报告基因检测系统中,无论是瞬时转染高表达的PXR还是CAR,甘草次酸都没有表现出对CYP2C19的诱导效应。Real-time PCR的实验结果与报告基因检测结果相一致。以1-羟咪达唑仑的生成率进行对CYP3A4活性检测,在转染了CAR的结肠癌细胞株LS174T,可以看到甘草次酸使CYP3A4的活性增加。
结论：甘草酸没有通过核受体PXR、CAR对CYP3A4和CYP2C19的转录表达产生影响。甘草次酸通过CAR和／或PXR途径,主要在肠道提高CYP3A4的转录活性。
背景：甘草是一种天然药物,因为有着多种药物效应而被临床广泛应用,随着与临床常用药物合用的情况日益增加,它们之间产生药物相互作用的几率也逐渐增高。甘草酸是甘草的主要成分,由于它具备保肝抗炎、抗病毒、抗氧化等作用被临床广泛应用,如常用作各种慢性肝炎、支气管炎和艾滋病的辅助治疗,因而甘草酸制剂不可避免地需要长期大剂量的服用。甘草酸对体内CYP450酶的影响值得关注。我们先前应用COCKTAIL方法发现口服甘草酸制剂对体内CYP3A酶活性具有诱导作用,并且报告基因检测发现甘草次酸通过核受体使CYP3A4转录活性增加,但甘草酸制剂的服用是否影响临床药物药代动力学而影响治疗尚未明确。奥美拉唑为质子泵抑制剂,临床常用于治疗消化性溃疡等疾病,在体内主要由CYP2C19和CYP3A4介导代谢为5-羟奥美拉唑和奥美拉唑砜,因此考察两者合用可能发生的药物相互作用对临床合理用药具有一定的指导意义。本课题选取奥美拉唑为代表,观察在临床合并治疗时,甘草酸对治疗药物与其代谢产物药代动力学的影响。
目的：用CYP3A4和CYP2C19的共同探药奥美拉唑观察人体内甘草酸对CYP2C19和CYP3A4酶活性的影响,判断其效应与CYP2C19基因型之间的相关性,并观察甘草酸与奥美拉唑的中西药相互作用。
方法：在297名无血缘关系汉族男性健康志愿者中分别采用聚合酶链式反应-限制性片断长度多态性(Polymerase Chain Reaction-Restriction Fragment Length Polymorphism, PCR-RFLP)方法检测CYP2C19*2或*3基因突变。选取健康受试者18人(野生型CYP2C19*1／*1,n=6；突变杂合子CYP2C19*1／*2or*3,n=6；突变纯合子CYP2C19*2／*2or*3,n=6)参加本次平行开放的两阶段随机交叉临床试验。每个阶段受试者服用甘草酸制剂(甘草甜素片)或安慰剂150mg,每天2次,连续服用14天,第15天受试者口服20mg奥美拉唑胶囊1粒,然后采集0-12小时外周静脉血。用高效液相色谱法测定各时间点血浆中奥美拉唑和代谢产物浓度。
结果：连续服用甘草酸14天后,血药奥美拉唑浓度显著降低,其代谢产物5-羟奥美拉唑血药浓度无明显变化而奥美拉唑砜血药浓度显著升高。奥美拉唑与5-羟奥美拉唑的比值在各基因型受试者中无显著变化。奥美拉唑与奥美拉唑砜的比值在CYP2C19*1／*1受试者中降低了43.93±13.56%(p=0.009),在CYP2C19*1／*2中降低了44.85±14.84%(p=0.002),在CYP2C19*2／*2中降低36.16±7.52%(p<0.001)。奥美拉唑与奥美拉唑砜的比值在不同基因型中的降低程度无显著差异
结论：甘草酸对CYP2C19介导的羟化活性没有显著影响,但能够诱导CYP3A4介导的奥美拉唑的磺化,导致奥美拉唑的血药浓度降低。
BACKGROUND:Cytochrome P450s superfamily expressed widely in organisms are known to play an important role in the biotransformation of many endogenous and exogenous substances. Inhibition or induction of cytochrome P450 isozymes is one of the major causes for clinical drug-drug interactions. Licorice and glycyrrhizin is widely used in the treatment of various diseases such as chronic hepatitis. Although licorice and glycyrrhizin are widely used, there is little study on its effects on CYP450 in human beings. To investigate medicines effect on CYP450s activities has important clinical significance, it helps with clinical rational administration and reducing the drug adverse reaction inducing by drug interactions. Glycyrrhizin obviously affects the activities of CYP450s in rat and mouths. However, as our knowledge,This is the first study to investigate the effects of glycyrrhizin on CYP450s in vivo.
OBJECTIVE:This study was designed to investigate the effects of glycyrrhizin on CYP3A, CYP1A2, CYP2E1, CYP2D6 activities in humans. The effect of glycyrrhizin on CYP activity in vivo was assessed by a four-drug cocktail approach useing CYP probe drugs midazolam(CYP3A), caffeine(CYP1A2), chlorzoxazone(CYP2E1) and metoprolol(CYP2D6).
METHODS:Twelve healthy adult men were enrolled in a 2-phase randomized crossover design. In each phase the volunteers received placebo or glycyrrhizin for 14 days.Then probe drug cocktails of midazolam, caffeine, chlorzoxazone and metoprolol were administered to determine in vivo CYP activities.
RESULTS:Glycyrrhizin administration significantly increased 1-hydroxymidazolam/midazolam serum ratios (1 hour sample) (p=0.021), Conversely, the plasma paraxanthine/caffeine ratios and 6-hydroxychlorzoxazone/chlorzoxazone plasma ratios were both significantly decreased by glycyrihizin treatment compared to placebo treatment (p=0.004, p=0.021).14 days glycyrrhizin treatment did not alter the urinary metoprolol/a-hydroxymetoprolol ratio (the index of CYP2D6 activity) (p= 0.248).
CONCLUSIONS:By utilizing single time-point phenotypic ratios, administration of glycyrrhizin resulted in an induction of CYP3A and a significant inhibit of CYP1A2 and CYP2E1 activity, and showed no significant effects on CYP2D6.
BACKGROUND:Glycyrrhizin is a major ingredient of licorice which is widely used in the treatment of various diseases such as chronic hepatitis. Licorice or glycyrrhizin have been shown to alter the activity of CYP3A in rodents. The influence of glycyrrhizin on CYP3A has not been elucidated in humans. This is the first report showing the effects of glycyrrhizin on CYP3A enzyme activity in humans.
OBJECTIVE:To investigate the effects of repeated glycyrrhizin ingestion on the oral pharmacokinetics of midazolam, a probe drug for CYP3A activity in humans. METHODS:Sixteen healthy adult male subjects were enrolled in a 2-phase randomized crossover design. In each phase the volunteers received placebo or glycyrrhizin for 14 days. On the 15th day, midazolam was administered as a probe drug to determine in vivo CYP3 A activity in vivo.
RESULTS:Glycyrrhizin administration decreased midazolam maximum plasma concentration(Cmax) by 12.4% (p<0.01; 95%CI:-28.86 to 4.03) and midazolam AUC0-∞by 20.2% (p<0.05; 95%CI:-31.76 to-8.66).Conversely, 1'-hydroxymidazolam Cmax was increased by 19.1% (p<0.01; 95%CI:10.6 to 27.7) and 1'-hydroxymidazolam AUC0-∞was increased by 20.3% (p<0.01; 95%CI:11.0 to 29.6) with glycyrrihizin. For AUC0-∞and Cmax of midzolam, the 90% CI for the geometric mean ratio of glycyrrhizin over placebo were both out of the no-effect boundaries of 0.80-1.25.
CONCLUSIONS:Administration of glycyrrhizin resulted in a modest induction of CYP3A with clinically relevant according to the bioequivalence analysis.
BACKGROUND:Traditional medicine licorice has been used as a medicinal plant for thousands of years.The active component of licorice, glycyrrhizin, is hydrolyzed in vivo to glycyrrhetinic acid, which is responsible for most of its pharmacological properties. Our previous clinical trial has shown that glycyrrhizin administration exerted inhibitive effects on the activities of CYP1A2 and CYP2E1, and inductive effect on CYP3A activity. However, the mechanism for glycyrrhizin's above effects has not been clarified.
OBJECTIVE:To find out whether glycyrrhizin and glycyrrhetic acid have effect on CYPs activities including CYP1A2, CYP3A4, CYP2C19, CYP2E1, and CYP2D6 in pooled human liver microsomes.
METHODS:The in vitro effects of glycyrrhizin and glycyrrhetic acid on CYP1A2 (caffeine deethylation), CYP3A (midazolam 1-hydroxylation), CYP2C19 (omeprazole 5'-hydroxylation), CYP3A4(omeprazole sulfoxidation), CYP2D6 (metoprololα-hydroxylation), and CYP2E1 (chlorzoxazone 6-hydroxylation) activities were examined using pooled human liver microsomes. The concentrations of the probe drugs and their metabolites were determined by HPLC and LC-MS/MS.
RESULTS:With concentrations up to 200μM, Glycyrrhizin showed no appreciable effect on CYP1A2, CYP3A, CYP2C19,CYP3A4, CYP2E1, and CYP2D6 activities. Glycyrrhetic acid potent inhibited CYP3A(midazolam 1-hydroxylation) activity with a IC50 value of 32.94±9.51μM. Glycyrrhetic acid exhibited somewhat smaller inhibitory effects on CYP2C19 (omeprazole 5'-hydroxylation) and CYP3A4(omeprazole sulfoxidation) activities, with IC50 values of 176.35±22.46μM and 141.28±22.46μM, respectively. Km and Vmax for midazolam 1'-hydroxylation by microsomes were 3.59±0.85μM and 2.78±0.18 nmol/min.mg, respectively. Formation of 1'-OH MDZ by CYP3A4 was noncompetitively inhibited by glycyrrhetic acid (GA), with a Ki of 7.38±0.93μM.
CONCLUSIONS:.Glycyrrhizin showed no effect on CYP1A2, CYP3A, CYP2C19, CYP3A4, CYP2E1, and CYP2D6 activities in human liver microsomes. Glycyrrhetic acid noncompetitively inhibits Formation of 1'-OH MDZ by CYP3A4, and also inhibit metabolism of omeprazole to 5'-Hydroxyomeprazole by CYP2C19 and inhibit metabolism of omeprazole to omeprazole sulfone by CYP3A4.
BACKGROUND:Research has found that licorice(Gan Cao) could induce total CYP450s in rodents. And previous reports have demonstrated that licorice(Gan Cao) total extracts activated PXR and induced the expression of drug-metabolism, however, the constituents responsible for licorice-mediated CYP450s induction and the underlying molecular mechanisms remains unknown. Our previous work has demonstrated that administration of glycyrrhizin in healthy males resulted in an increased metabolism of Midazolam, By contrast, glycyrrhetic acid presented play an inhibitive action in metabolism of midazolam in pooled human liver microsomes. We also observed inhibition metabolism of omeprazole to 5'-Hydroxyomeprazole by CYP2C19 in human liver microsomes. The discovery of a family of nuclear receptors such as pregnane X recepor (PXR) and constitutive androstane receptor(CAR) gives insight into the molecular explanation of CYP3A induction by glycyrrhizin. In the present study, interactions between glycyrrhizin and glycyrrhetic acid and human CAR and PXR were evaluated using a reporter gene assay.
OBJECTIVE:In our study, we tested the hypothesis whether glycyrrhizin or glycyrrhetic acid in therapeutic concentrations has potential to affect expression of CYP3A4 and CYP2C19 via constitutive androstane receptor(CAR) and pregnane X receptor(PXR) pathways.
METHODS:Interaction of glycyrrhizin and glycyrrhetic acid with CAR and PXR nuclear receptors was studied using luciferase reporter assays, real-time reverse transcriptase chain reaction (RT-PCR), and analysis of CYP3A4 catalytic activity.
RESULTS:Using transient transfection reporter assays in Caco2 cells, Glycyrrhetic acid was recognized to activate CYP3A4 promoter via CAR and PXR pathways. A significant effect of glycyrrhetic acid on CYP3A4 promoter activation in HepG2 cells was observed only by CAR pathway. Glycyrrhizin showed no impact on CYP3A4 promotor activation by CAR or PXR pathways. Neither glycyrrhizin nor glycyrrhetic acid have impacts on CYP2C19 promoter via CAR or PXR pathways. These data well correlated with up-regulation of CYP3A4 mRNA analyzed by real-time RT-PCR in cells with expression vectors encoding CAR or PXR and treated with glycyrrhetic acid. In addition, analysis of specific CYP3A4 catalytic activity revealed its significant increase in glycyrrhetic acid-treated LS174T transfected with CAR.
CONCLUSIONS:.In conclusions,we provide novel insight into the mechanism by which GA affects gene expression of CYP3A4. Our results demonstrate that GA has potential to up-regulate CYP3A4 through direct activation of CAR and/or PXR pathways.
OBJECTIVE:To investigate the interaction between glycyrrhizin and omeprazole and observe the effects of glycyrrhizin on CYP2C19 and CYP3A4 activities in healthy Chinese male volunteers with different CYP2C19 genotypes..
METHODS:Eighteen healthy subjects (six CYP2C19*1/*1, five CYP2C19*1/*2, one CYP2C19*1/*3, five CYP2C19*2/*2 and one CYP2C19*2/*3) were enrolled in a two-phase randomized crossover trial. In each phase, all subjects received placebo or glycyrrhizin salt tablet 150mg twice daily for 14 consecutive days. The pharmacokinetics of omeprazole(20mg orally on day 15) was determined for up to 12h following administration by HPLC.
RESULTS:After 14-day treatment of glycyrrhizin, plasma omeprazole significantly decreased, and those of omeprazole sulfone significantly increased. However, plasma concenetrations of 5-hydroxyomeprazole did not significantly change. The ratio of AUC0-∞of omeprazole to omeprazole sulfone decreased by 43.93±13.56%(p=0.009) in CYP2C19*1/*1,44.85±14.84%(p=0.002) in CYP2C19*1/*2or*3 and 36.16±7.52%(p＜0.001) in CYP2C19*2/*2 or*3 while those of omeprazole to 5-hydroxyomeprazole did not change significantly in all three genotypes. No significant differences in glycyrrhizin response were found among CYP2C19 genotypes..
CONCLUSIONS:Glycyrrhizin induces CYP3A4-catalyzed sulfoxidation of omeprazole and leads to decreased omeprazole plasma concentrations, but has no significant impact on CYP2C19-dependent hydroxylation of omeprazole.
目的：检测甘草的主要成分甘草酸对人体内CYP3A、CYP1A2、CYP2E1、CYP2D6活性的影响。
方法：应用COCKTAIL方法及单点法在人体内初步筛查甘草酸对人体内CYP3A、CYP1A2、CYP2E1、CYP2D6活性的影响。征集12名健康男性志愿者,加入双周期交叉实验,每周期受试者接受甘草酸或安慰剂处理14天,第15天同时服用探药咪达唑仑、咖啡因、氯唑沙宗和美托洛尔,采集单点外周静脉血及收集尿样来检测各时间点相应的药物及相应代谢产物的浓度。
结果：服用甘草酸两周使1小时血浆中1-羟基咪达唑仑和咪达唑仑的比值显著升高(p=0.021),但是却显著降低6小时17X/137X的浓度之比(p=0.004)以及4小时6-羟基氯唑沙宗／氯唑沙宗的比值(p=0.021)；甘草酸处理对0-8小时尿样中美托洛尔与α-羟基美托洛尔浓度的比值没有影响(p=0.248),
结论：口服甘草酸14天能够诱导体内CYP3A酶活性；对CYP1A2、CYP2E1酶活性有抑制作用。甘草酸的服用对CYP2D6酶活性没有明显影响。
背景：甘草及甘草酸的应用日益广泛,尤其现代用于慢性肝炎的治疗,剂量增加及疗程延长,其与其他药物合用的机会增加,但是其对人体内CYP450酶的影响却未见报道。我们第一部分用鸡尾酒法和单点法研究显示甘草酸能够诱导CYP3A酶,但是由于单点法的限制,甘草酸对CYP3A的诱导程度以及对咪达唑仑的药代动力学参数的影响和可能发生的临床药物相互作用还是未知的。
目的：应用CYP3A最经典探药咪达唑仑进一步探讨甘草酸对人体内CYP3A酶活性的影响,并观察甘草酸对咪达唑仑药代动力学的影响及其可能的甘草酸与咪达唑仑的药物相互作用。
方法：征集16名健康男性志愿者,加入双周期交叉实验,每周期受试者接受甘草酸或安慰剂处理14天,第15天同时服用探药咪达唑仑7.5mg,收集O-12小时血样,LC-MS/MS方法检测血浆中咪达唑仑及其代谢产物1-羟基咪达唑仑的药物浓度。
结果：服用甘草酸两周使咪达唑仑Cmax显著降低12%(p<0.01；95%CI：-28.86 to 4.03)；相应的咪达唑仑AUC0-∞显著降低by 20.2%(p<0.05；95%CI：-31.76 to-8.66)。而1-羟基咪达唑仑Cmax明显升高19.1%(p<0.01；95%CI：10.6 to27.7)；1-羟基咪达唑仑AUC0-∞显著增加20.3%(p<0.01；95%CI：11.0 to 29.6)。对咪达唑仑的药代动力学参数AUC0-∞和Cmax进行生物等效性分析,其90%可信区间均超出0.8-1.25的生物等效范围.
结论：长期(14天)的甘草酸的服用诱导体内CYP3A酶活性,使体内咪达唑仑的药代动力学参数发生变化,生物等效性分析超出等效范围具有临床意义。
背景：传统中药甘草的主要成分有甘草酸、甘草次酸、甘草黄酮、多羟基酚等成分。水溶性提取物中甘草酸是主要成分,有少量甘草次酸。但甘草酸口服后主要经肠道酶作用水解转化为甘草次酸吸收入血。我们前面临床实验证实口服甘草酸能够诱导体内CYP3A活性,抑制CYP1A2及CYP2E1活性,而对CYP2D6活性无影响,为了探讨其作用机制,我们首先拟在肝微粒体水平探讨甘草酸及其水解产物甘草次酸对CYP450酶的直接作用效应。
目的：研究甘草酸及甘草次酸对人肝微粒体中CYP 1 A2、CYP3A4、CYP2C19、CYP2E1、CYP2D6酶活性的影响。
方法：用体外实验人肝微粒体孵化体系的方法,分别以咖啡因、咪哒唑仑、奥美拉唑、氯唑沙宗、美托洛尔为探针药,利用HPLC方法测定探针药与相应代谢产物的浓度,以代谢产物的产率为酶活性指标,评估甘草酸及甘草次酸在人肝微粒体孵化体系中对CYP1A2、CYP3A、CYP2C19、CYP3A4、CYP2D6、CYP2E1酶活性的影响。为揭开甘草酸对人体内P450酶的作用机制提供有益信息。
结果：在人肝微粒体反应体系中,甘草酸(0-200μM)对CYP1A2、CYP3A4、CYP2C19、CYP2E1、CYP2D6酶活性均无明显影响。同时观察到甘草次酸自10μM浓度开始对CYP3A介导的l羟咪达唑仑的生成和CYP3A4介导的奥美拉唑磺化作用均有明显抑制效应,且随着甘草次酸浓度的升高,对酶的抑制作用加强,其IC50值分别是32.94±9.51、141.28±22.46μM。甘草次酸自25μM浓度开始抑制CYP2C19介导的奥美拉唑羟化作用,IC50值为176.35±22.46μM。酶促动力学分析,甘草次酸对CYP3A催化的咪达唑仑1’羟化作用的抑制类型为非竞争性抑制,抑制常数为7.38±0.93μM。
结论：甘草酸在肝微粒体水平,对CYP1A2、CYP3A、CYP2C19、CYP3A4、CYP2D6、CYP2E 1酶活性无明显影响。甘草次酸非竞争性抑制CYP3A介导的咪达唑仑1位羟化活性,对CYP3A4介导的奥美拉唑磺化和CYP2C19介导的羟化有明显的抑制作用。
背景：以往研究表明甘草能够提高啮齿动物肝脏中多种CYP450酶的活性,并且甘草水溶性提取物是人PXR激动剂。但是甘草中何种成分对CYP450酶产生影响及何种成分激动PXR及其分子机制都不清楚。与此相一致的,我们前面的体内实验表明口服甘草酸会引起人体内CYP3A酶活性的增加,而肝微粒体实验却表明甘草次酸非竞争性抑制CYP3A4酶。为进一步探讨其体内诱导机制,我们拟从核受体PXR、CAR的调控角度来分析,观察甘草酸或甘草次酸是否通过核受体影响CYP3A基因表达而使体内酶活性增加。肝微粒体实验观察到甘草次酸抑制CYP2C19酶活性,为了正确预测口服甘草酸对体内CYP2C19活性的影响,我们也观察甘草酸或甘草次酸是否通过核受体对CYP2C19的调控产生影响。
目的：观察甘草酸及甘草次酸是否通过孕烷核受体PXR或激活组成性核受体CAR途径,诱导细胞色素CYP3A4、CYP2C19的转录表达。
方法：在人肝肿瘤细胞株HepG2细胞和人结肠癌细胞株Caco2细胞中,用瞬时转染报告基因试验检测甘草酸及甘草次酸对核受体PXR或CAR介导的CYP3A4、CYP2C19的转录调节作用。同时应用Real-time PCR检验甘草次酸对高表达PXR/RXRa或CAR/RXRa的肠道上皮肿瘤细胞株中CYP3A4mRNA表达的影响,并应用LC-MS/MS方法检测甘草次酸引起的CYP3A4活性的变化。为揭开并预测甘草及甘草酸对人体内CYP3A4及CYP2C19的影响和作用机制提供有益信息。
结果：在瞬时转染的报告基因试验中,甘草酸不通过核受体PXR或CAR对CYP3A4或CYP2C19的转录表达产生影响。而甘草次酸在超高表达PXR和RXRa的肠道腺癌细胞株Caco2细胞中,能够引起CYP3A4的转录表达增加,而在超高表达PXR和RXRa的肝脏的肝癌细胞株HepG2细胞中,甘草次酸没有表现诱导CYP3A4转录表达的作用。无论在肝脏还是肠道肿瘤细胞株,甘草次酸均表现通过CAR诱导CYP3A4的转录表达。在同样的瞬时转染的报告基因检测系统中,无论是瞬时转染高表达的PXR还是CAR,甘草次酸都没有表现出对CYP2C19的诱导效应。Real-time PCR的实验结果与报告基因检测结果相一致。以1-羟咪达唑仑的生成率进行对CYP3A4活性检测,在转染了CAR的结肠癌细胞株LS174T,可以看到甘草次酸使CYP3A4的活性增加。
结论：甘草酸没有通过核受体PXR、CAR对CYP3A4和CYP2C19的转录表达产生影响。甘草次酸通过CAR和／或PXR途径,主要在肠道提高CYP3A4的转录活性。
背景：甘草是一种天然药物,因为有着多种药物效应而被临床广泛应用,随着与临床常用药物合用的情况日益增加,它们之间产生药物相互作用的几率也逐渐增高。甘草酸是甘草的主要成分,由于它具备保肝抗炎、抗病毒、抗氧化等作用被临床广泛应用,如常用作各种慢性肝炎、支气管炎和艾滋病的辅助治疗,因而甘草酸制剂不可避免地需要长期大剂量的服用。甘草酸对体内CYP450酶的影响值得关注。我们先前应用COCKTAIL方法发现口服甘草酸制剂对体内CYP3A酶活性具有诱导作用,并且报告基因检测发现甘草次酸通过核受体使CYP3A4转录活性增加,但甘草酸制剂的服用是否影响临床药物药代动力学而影响治疗尚未明确。奥美拉唑为质子泵抑制剂,临床常用于治疗消化性溃疡等疾病,在体内主要由CYP2C19和CYP3A4介导代谢为5-羟奥美拉唑和奥美拉唑砜,因此考察两者合用可能发生的药物相互作用对临床合理用药具有一定的指导意义。本课题选取奥美拉唑为代表,观察在临床合并治疗时,甘草酸对治疗药物与其代谢产物药代动力学的影响。
目的：用CYP3A4和CYP2C19的共同探药奥美拉唑观察人体内甘草酸对CYP2C19和CYP3A4酶活性的影响,判断其效应与CYP2C19基因型之间的相关性,并观察甘草酸与奥美拉唑的中西药相互作用。
方法：在297名无血缘关系汉族男性健康志愿者中分别采用聚合酶链式反应-限制性片断长度多态性(Polymerase Chain Reaction-Restriction Fragment Length Polymorphism, PCR-RFLP)方法检测CYP2C19*2或*3基因突变。选取健康受试者18人(野生型CYP2C19*1／*1,n=6；突变杂合子CYP2C19*1／*2or*3,n=6；突变纯合子CYP2C19*2／*2or*3,n=6)参加本次平行开放的两阶段随机交叉临床试验。每个阶段受试者服用甘草酸制剂(甘草甜素片)或安慰剂150mg,每天2次,连续服用14天,第15天受试者口服20mg奥美拉唑胶囊1粒,然后采集0-12小时外周静脉血。用高效液相色谱法测定各时间点血浆中奥美拉唑和代谢产物浓度。
结果：连续服用甘草酸14天后,血药奥美拉唑浓度显著降低,其代谢产物5-羟奥美拉唑血药浓度无明显变化而奥美拉唑砜血药浓度显著升高。奥美拉唑与5-羟奥美拉唑的比值在各基因型受试者中无显著变化。奥美拉唑与奥美拉唑砜的比值在CYP2C19*1／*1受试者中降低了43.93±13.56%(p=0.009),在CYP2C19*1／*2中降低了44.85±14.84%(p=0.002),在CYP2C19*2／*2中降低36.16±7.52%(p<0.001)。奥美拉唑与奥美拉唑砜的比值在不同基因型中的降低程度无显著差异
结论：甘草酸对CYP2C19介导的羟化活性没有显著影响,但能够诱导CYP3A4介导的奥美拉唑的磺化,导致奥美拉唑的血药浓度降低。
BACKGROUND:Cytochrome P450s superfamily expressed widely in organisms are known to play an important role in the biotransformation of many endogenous and exogenous substances. Inhibition or induction of cytochrome P450 isozymes is one of the major causes for clinical drug-drug interactions. Licorice and glycyrrhizin is widely used in the treatment of various diseases such as chronic hepatitis. Although licorice and glycyrrhizin are widely used, there is little study on its effects on CYP450 in human beings. To investigate medicines effect on CYP450s activities has important clinical significance, it helps with clinical rational administration and reducing the drug adverse reaction inducing by drug interactions. Glycyrrhizin obviously affects the activities of CYP450s in rat and mouths. However, as our knowledge,This is the first study to investigate the effects of glycyrrhizin on CYP450s in vivo.
OBJECTIVE:This study was designed to investigate the effects of glycyrrhizin on CYP3A, CYP1A2, CYP2E1, CYP2D6 activities in humans. The effect of glycyrrhizin on CYP activity in vivo was assessed by a four-drug cocktail approach useing CYP probe drugs midazolam(CYP3A), caffeine(CYP1A2), chlorzoxazone(CYP2E1) and metoprolol(CYP2D6).
METHODS:Twelve healthy adult men were enrolled in a 2-phase randomized crossover design. In each phase the volunteers received placebo or glycyrrhizin for 14 days.Then probe drug cocktails of midazolam, caffeine, chlorzoxazone and metoprolol were administered to determine in vivo CYP activities.
RESULTS:Glycyrrhizin administration significantly increased 1-hydroxymidazolam/midazolam serum ratios (1 hour sample) (p=0.021), Conversely, the plasma paraxanthine/caffeine ratios and 6-hydroxychlorzoxazone/chlorzoxazone plasma ratios were both significantly decreased by glycyrihizin treatment compared to placebo treatment (p=0.004, p=0.021).14 days glycyrrhizin treatment did not alter the urinary metoprolol/a-hydroxymetoprolol ratio (the index of CYP2D6 activity) (p= 0.248).
CONCLUSIONS:By utilizing single time-point phenotypic ratios, administration of glycyrrhizin resulted in an induction of CYP3A and a significant inhibit of CYP1A2 and CYP2E1 activity, and showed no significant effects on CYP2D6.
BACKGROUND:Glycyrrhizin is a major ingredient of licorice which is widely used in the treatment of various diseases such as chronic hepatitis. Licorice or glycyrrhizin have been shown to alter the activity of CYP3A in rodents. The influence of glycyrrhizin on CYP3A has not been elucidated in humans. This is the first report showing the effects of glycyrrhizin on CYP3A enzyme activity in humans.
OBJECTIVE:To investigate the effects of repeated glycyrrhizin ingestion on the oral pharmacokinetics of midazolam, a probe drug for CYP3A activity in humans. METHODS:Sixteen healthy adult male subjects were enrolled in a 2-phase randomized crossover design. In each phase the volunteers received placebo or glycyrrhizin for 14 days. On the 15th day, midazolam was administered as a probe drug to determine in vivo CYP3 A activity in vivo.
RESULTS:Glycyrrhizin administration decreased midazolam maximum plasma concentration(Cmax) by 12.4% (p<0.01; 95%CI:-28.86 to 4.03) and midazolam AUC0-∞by 20.2% (p<0.05; 95%CI:-31.76 to-8.66).Conversely, 1'-hydroxymidazolam Cmax was increased by 19.1% (p<0.01; 95%CI:10.6 to 27.7) and 1'-hydroxymidazolam AUC0-∞was increased by 20.3% (p<0.01; 95%CI:11.0 to 29.6) with glycyrrihizin. For AUC0-∞and Cmax of midzolam, the 90% CI for the geometric mean ratio of glycyrrhizin over placebo were both out of the no-effect boundaries of 0.80-1.25.
CONCLUSIONS:Administration of glycyrrhizin resulted in a modest induction of CYP3A with clinically relevant according to the bioequivalence analysis.
BACKGROUND:Traditional medicine licorice has been used as a medicinal plant for thousands of years.The active component of licorice, glycyrrhizin, is hydrolyzed in vivo to glycyrrhetinic acid, which is responsible for most of its pharmacological properties. Our previous clinical trial has shown that glycyrrhizin administration exerted inhibitive effects on the activities of CYP1A2 and CYP2E1, and inductive effect on CYP3A activity. However, the mechanism for glycyrrhizin's above effects has not been clarified.
OBJECTIVE:To find out whether glycyrrhizin and glycyrrhetic acid have effect on CYPs activities including CYP1A2, CYP3A4, CYP2C19, CYP2E1, and CYP2D6 in pooled human liver microsomes.
METHODS:The in vitro effects of glycyrrhizin and glycyrrhetic acid on CYP1A2 (caffeine deethylation), CYP3A (midazolam 1-hydroxylation), CYP2C19 (omeprazole 5'-hydroxylation), CYP3A4(omeprazole sulfoxidation), CYP2D6 (metoprololα-hydroxylation), and CYP2E1 (chlorzoxazone 6-hydroxylation) activities were examined using pooled human liver microsomes. The concentrations of the probe drugs and their metabolites were determined by HPLC and LC-MS/MS.
RESULTS:With concentrations up to 200μM, Glycyrrhizin showed no appreciable effect on CYP1A2, CYP3A, CYP2C19,CYP3A4, CYP2E1, and CYP2D6 activities. Glycyrrhetic acid potent inhibited CYP3A(midazolam 1-hydroxylation) activity with a IC50 value of 32.94±9.51μM. Glycyrrhetic acid exhibited somewhat smaller inhibitory effects on CYP2C19 (omeprazole 5'-hydroxylation) and CYP3A4(omeprazole sulfoxidation) activities, with IC50 values of 176.35±22.46μM and 141.28±22.46μM, respectively. Km and Vmax for midazolam 1'-hydroxylation by microsomes were 3.59±0.85μM and 2.78±0.18 nmol/min.mg, respectively. Formation of 1'-OH MDZ by CYP3A4 was noncompetitively inhibited by glycyrrhetic acid (GA), with a Ki of 7.38±0.93μM.
CONCLUSIONS:.Glycyrrhizin showed no effect on CYP1A2, CYP3A, CYP2C19, CYP3A4, CYP2E1, and CYP2D6 activities in human liver microsomes. Glycyrrhetic acid noncompetitively inhibits Formation of 1'-OH MDZ by CYP3A4, and also inhibit metabolism of omeprazole to 5'-Hydroxyomeprazole by CYP2C19 and inhibit metabolism of omeprazole to omeprazole sulfone by CYP3A4.
BACKGROUND:Research has found that licorice(Gan Cao) could induce total CYP450s in rodents. And previous reports have demonstrated that licorice(Gan Cao) total extracts activated PXR and induced the expression of drug-metabolism, however, the constituents responsible for licorice-mediated CYP450s induction and the underlying molecular mechanisms remains unknown. Our previous work has demonstrated that administration of glycyrrhizin in healthy males resulted in an increased metabolism of Midazolam, By contrast, glycyrrhetic acid presented play an inhibitive action in metabolism of midazolam in pooled human liver microsomes. We also observed inhibition metabolism of omeprazole to 5'-Hydroxyomeprazole by CYP2C19 in human liver microsomes. The discovery of a family of nuclear receptors such as pregnane X recepor (PXR) and constitutive androstane receptor(CAR) gives insight into the molecular explanation of CYP3A induction by glycyrrhizin. In the present study, interactions between glycyrrhizin and glycyrrhetic acid and human CAR and PXR were evaluated using a reporter gene assay.
OBJECTIVE:In our study, we tested the hypothesis whether glycyrrhizin or glycyrrhetic acid in therapeutic concentrations has potential to affect expression of CYP3A4 and CYP2C19 via constitutive androstane receptor(CAR) and pregnane X receptor(PXR) pathways.
METHODS:Interaction of glycyrrhizin and glycyrrhetic acid with CAR and PXR nuclear receptors was studied using luciferase reporter assays, real-time reverse transcriptase chain reaction (RT-PCR), and analysis of CYP3A4 catalytic activity.
RESULTS:Using transient transfection reporter assays in Caco2 cells, Glycyrrhetic acid was recognized to activate CYP3A4 promoter via CAR and PXR pathways. A significant effect of glycyrrhetic acid on CYP3A4 promoter activation in HepG2 cells was observed only by CAR pathway. Glycyrrhizin showed no impact on CYP3A4 promotor activation by CAR or PXR pathways. Neither glycyrrhizin nor glycyrrhetic acid have impacts on CYP2C19 promoter via CAR or PXR pathways. These data well correlated with up-regulation of CYP3A4 mRNA analyzed by real-time RT-PCR in cells with expression vectors encoding CAR or PXR and treated with glycyrrhetic acid. In addition, analysis of specific CYP3A4 catalytic activity revealed its significant increase in glycyrrhetic acid-treated LS174T transfected with CAR.
CONCLUSIONS:.In conclusions,we provide novel insight into the mechanism by which GA affects gene expression of CYP3A4. Our results demonstrate that GA has potential to up-regulate CYP3A4 through direct activation of CAR and/or PXR pathways.
OBJECTIVE:To investigate the interaction between glycyrrhizin and omeprazole and observe the effects of glycyrrhizin on CYP2C19 and CYP3A4 activities in healthy Chinese male volunteers with different CYP2C19 genotypes..
METHODS:Eighteen healthy subjects (six CYP2C19*1/*1, five CYP2C19*1/*2, one CYP2C19*1/*3, five CYP2C19*2/*2 and one CYP2C19*2/*3) were enrolled in a two-phase randomized crossover trial. In each phase, all subjects received placebo or glycyrrhizin salt tablet 150mg twice daily for 14 consecutive days. The pharmacokinetics of omeprazole(20mg orally on day 15) was determined for up to 12h following administration by HPLC.
RESULTS:After 14-day treatment of glycyrrhizin, plasma omeprazole significantly decreased, and those of omeprazole sulfone significantly increased. However, plasma concenetrations of 5-hydroxyomeprazole did not significantly change. The ratio of AUC0-∞of omeprazole to omeprazole sulfone decreased by 43.93±13.56%(p=0.009) in CYP2C19*1/*1,44.85±14.84%(p=0.002) in CYP2C19*1/*2or*3 and 36.16±7.52%(p＜0.001) in CYP2C19*2/*2 or*3 while those of omeprazole to 5-hydroxyomeprazole did not change significantly in all three genotypes. No significant differences in glycyrrhizin response were found among CYP2C19 genotypes..
CONCLUSIONS:Glycyrrhizin induces CYP3A4-catalyzed sulfoxidation of omeprazole and leads to decreased omeprazole plasma concentrations, but has no significant impact on CYP2C19-dependent hydroxylation of omeprazole.
引文
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