【作者】 雷和平；

【导师】 周宏灏；

【作者基本信息】 中南大学 ， 药理学， 2009， 博士

【摘要】 中草药用于疾病治疗和保健的历史悠久。一般认为天然药物比合成药物安全导致中草药在世界范围内的使用越来越广泛,但中草药同样具有潜在的药物相互作用。一些中草药可能诱导或抑制肝脏细胞色素P450(CYP)药物代谢酶,从而引起自身及其他合用药物代谢的改变,可能导致药物不良反应和药物相互作用。因此,为了公众的安全,有必要深入研究中草药-西药间相互作用,特别是对常用的中草药的研究显得尤为重要。银杏叶提取物(Ginkgo biloba extract,GBE)是目前使用最为广泛的中草药之一。银杏叶提取物具有抗氧化、清除自由基、抗血小板活化因子、调节血管活性、增加血流量、神经保护等主要药理作用。银杏叶提取物与其他药物合用是否产生药物相互作用得到关注。银杏叶提取物与其他药物合用,可能通过影响肝药酶的活性发生药物相互作用,其中银杏叶提取物对肝药酶的诱导或抑制作用的研究较为深入。有报道银杏可以诱导健康受试者中奥美拉唑的羟化代谢,并与CYP2C19基因型相关。因而,当银杏与奥美拉唑或与CYP2C19的其他底物如伏立康唑合用时,有可能导致后者血药浓度降低及治疗失败。伏立康唑是一种广谱的三唑类抗真菌药,主要适用于治疗严重的真菌感染。伏立康唑主要经CYP2C19、CYP3A4代谢,少量经CYP2C9代谢。CYP2C19呈现遗传多态性,根据该酶活性大小,人群有强代谢者(EM_S)和弱代谢者(PM_S)之分。有报道银杏叶提取物能极大地增加大鼠肝脏的CYP酶的含量和CYP2B mRNA的表达,摄入银杏叶提取物也可诱导大鼠肝脏多种CYP酶的表达,尤其是CYP2B型酶的表达。贯叶连翘(St John’s wort,SJW)是一种常用来治疗轻到中度抑郁症的植物提取药。1998年,贯叶连翘在欧洲的销售额达到了60亿美元。作为一种传统的天然制剂,贯叶连翘一直被认为是安全有效药物。然而,自1998年以来,陆续的病例报告和临床研究表明,贯叶连翘有明显的药物相瓦作用,其中包括免疫抑制剂环孢霉素A和他克莫司,抗癌药伊马替尼,抗高血压药维拉帕米和他林洛尔、抗抑郁药阿米替林、抗真菌药伏立康唑等。贯叶连翘对CYP450药物代谢酶的诱导是该药导致临床常见药物相互作用的重要原因。孕激素受体(pergnanex receptor,PXR)为核受体超家族成员,主要在肠道与肝脏组织中表达。贯叶连翘是一种作用显著的诱导剂,其中含有孕激素受体PXR激动物质如贯叶金丝桃素,并通过PXR诱导靶基因表达,使CYP2B6表达增强。安非他酮是一种抗抑郁药和戒烟药,主要通过CYP2B6代谢成羟化安非他酮。因安非他酮是CYP2B6的底物,我们推测当与CYP2B6的诱导剂如银杏叶提取物和贯叶连翘合用时安非他酮的药代动力学可能会受到。一定程度影响。基于以上研究背景,本课题旨在CYP2C19强代谢者和弱代谢者中研究CYP2C19诱导剂银杏叶提取物对伏立康唑药动学的影响;研究两大广泛应用的中草药银杏叶提取物和贯叶连翘对CYP2B6的底物安非他酮药动学的影响。为伏立康唑和安非他酮的临床合理应用提供理论基础。本课题的主要研究结果如下:1.本文研究了银杏叶提取物对健康男性受试者体内伏立康唑药代动力学的影响。通过CYP2C19强代谢者和弱代谢者伏立康唑单用和银杏叶提取物与伏立康唑合用的自身对照研究证明,银杏叶提取物120mg一天两次共服用12天后,银杏叶提取物对伏立康唑的主要药动学参数药时曲线下面积、最大血药浓度、半衰期无明显影响,其血药浓度曲线接近,差异无显著性,提示健康受试者口服银杏后没有对单剂量伏立康唑的代谢产生重大的影响。此外,本次研究的结果再次证实了在CYP2C19野生型纯合子与突变型纯合子之间其底物伏立康唑的药物代谢动力学特征存在显著性差异。2.本文研究了银杏叶提取物对健康男性受试者体内安非他酮药代动力学的影响。研究结果表明连续服用14天银杏叶提取物前后,安非他酮的AUC和清除率以及羟化安非他酮的AUC无显著性改变(P＞0.05),提示银杏叶提取物对健康受试者体内安非他酮的代谢不会产生极大的影响。3.本课题研究的目的是在健康受试者中探讨连续口服贯叶连翘(325mg/次,一天三次)14天后对单剂量安非他酮药代动力学的影响。主要的结果是首次发现14天的贯叶连翘治疗可极大地增加安非他酮的清除并相应地降低了安非他酮的AUC(P＜0.05)。总之,本项目在健康受试者中研究银杏叶提取物对伏立康唑药动学的影响及银杏叶提取物和贯叶连翘对安非他酮药动学的影响,有利于中草药基础理论的深入和发展,同时为临床合理使用伏立康唑和安非他酮提供了实验依据和理论指导。更多还原

【Abstract】 Botanically derived therapies have been used for a variety of ailments for thousands of years. The belief that natural products are much safer than synthetic drugs and the use of herbal medicines has become increasingly popular throughout the world. Like synthetic drugs, herbal preparations also have potential to cause drug interactions. Some of these drugs can inhibit or induce liver cytochrome P450 activity. Thereby influence drug metabolism and maybe cause drug adverse action and drug interactions. Thus, for public safety there is a need to carefully study herb-drug interactions, especially for commonly used herbal products.Ginkgo biloba extract （GBE） is a popular herbal medicine and has received great attention in clinical therapy. Ginkgo biloba extract has some pharmacological functions, such as antioxidant, scavenging free radicals, anti-platelet-activating factor, the regulation of vascular activity, increased blood flow, neuroprotection. Interactions between GBE and other drugs are of increasing concern. Among these interaction,induction and inhibition of hepatic drug metabolizing enzymes by GBE have been investigated. Ginkgo biloba was shown to induce omeprazole hydroxylation in a CYP2C19 genotype-dependent manner in healthy male subjects. Therefore, Coadministration of Ginkgo biloba with omeprazole or other CYP2C19 substrates, like voriconazole, may reduce plasma voriconazole to subtherapeutic concentrations and in total loss of therapeutic effect.Voriconazole （VRC） is a new triazole broad spectrum second generation antifungal drug approved for systemic treatment of severe fungal infections. Voriconazole undergoes an extensive oxidative metabolism involving cytochrome P450 （CYP） enzyme isoforms CYP2C19, CYP3A4, and to a lesser extent, CYP2C9. CYP2C19 is characterised by a genetic polymorphism. According to their ability to express CYP2C19 and consequently according to the actual isoenzyme activity, individuals can be characterised as extensive metabolisers （homozygous and heterozygous EMs） and poor metabolisers （PMs）.Studies have reported that ginkgo biloba administration to rats markedly increased the CYP content and CYP2B mRNA in the liver and intake of ginkgo biloba also induced various hepatic CYP enzymes, especially CYP2B-type enzymes.St John’s wort （SJW） extracts have become popular natural medicines for the treatment of mild-to-moderate depression. Total sales of St John’s wort in Europe were approximately $6 billion （US） in 1998. Because it is a conventional herbal drug available over the counter, it is often regarded as safe by the public. However, since 1998, one after another clinically relevant SJW-drug interactions, including numerous case reports and clinical studies, have been reported, such as the immunosuppressants cyclosporine and tacrolimus, the anticancer drug imatinib, the antihypertensive agent verapamil and talinolol, the antidepressant amitriptyline, the antifungal agent voriconazole, et al.Induction of cytochrome P450 isozynres is the major cause for clinical drug interactions of St John’s wort. Pergnane x receptor, belonging to nuclear receptor superfamily, is mainly expressed in intestine and liver. SJW, in particular its active component hyperforin, activates PXR, thereby inducing CYP2B6 expression.Bupropion, an antidepressant and smoking cessation drug, is metabolized to its active metabolite hydroxybupropion almost exclusively by CYP2B6.As bupropion is a substrate for CYP2B6, it has the potential to interact with co-administered drugs that are inducers of this enzyme.Based on above information, our study was aimed to examine the possible effects of Ginkgo biloba extract as an inducer of CYP2C19 on single-dose pharmacokinetics of voriconazole in Chinese volunteers genotyped as either CYP2C19 extensive or poor metabolizers. To assess the effects of the two popular herbal products Ginkgo biloba extract and St John’s wort on the pharmacokinetics of bupropion in healthy volunteers. In order to provide useful information for the clinical use of voriconazole and bupropion.The present series of studies have found that:1. This is the study investigating the potential effect of Ginkgo biloba administration on the metabolism of voriconazole. Our results show that administration of Ginkgo biloba 120 mg twice daily for 12 days to CYP2C19 extensive metabolizers and poor metabolizers had no statistically significant effect on the pharmacokinetics of single-dose voriconazole, as measured by AUC, which suggests that Ginkgo biloba does not significantly affect the metabolism of voriconazole following a single oral dose in healthy Chinese males. A wide interindividual variability between different CYP2C19 genotypes was also seen in the control phase in the AUC_0-∞ of voriconazole after administration of a single oral dose.2. The present study was undertaken to investigate the effects of oral administration of ginkgo biloba extract on the pharmacokinetics of bupropion in healthy volunteers. Our results show administration of ginkgo biloba（120mg, bid） for 14 days had no statistically significant effect on the pharmacokinetics of bupropion or its active metabolite hydroxybupropion, as measured by AUC, which suggests ginkgo biloba does not significantly affect the metabolism of bupropion following a single oral dose in healthy Chinese males.3. In this study, we evaluated the effect of St John’s wort on oral bupropion pharmacokinetics in healthy volunteers before and after long-term consumption of St John’s wort （325mg 3 times a day for 14 days）.The major finding was that 14-days’ treatment with St John’s wort causes a significant increase in bupropion clearance and a significant decrease in bupropion AUC （P<0.05）.Through in-depth study of herbal drugs on the impact of drug metabolism, basic theories of herbal drugs is conductive to the deepening and development, and also provided useful information for the clinical use of voriconazole and bupropion.更多还原