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A study to investigate the mechanisms of Danshen-drug interactions using cytochrome P450 probe substrates.

机译：利用细胞色素P450探针底物研究丹参药物相互作用的机制的研究。

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摘要

Danshen, the dried root of Salvia miltiorrhiza Bunge, is a herb listed in the Chinese Pharmacopoeia for the treatment of cardiovascular and cerebrovascular diseases. Danshen has been reported to have antiplatelet, cardioprotective, anti-inflammatory, hepatoprotective, and anti-HIV effects in preclinical studies. However, exaggerated anticoagulation and bleeding complications have also been observed during concurrent use of Danshen and warfarin in patients, although the mechanism(s) of the herb-drug interaction, pharmacodynamic and/or pharmacokinetic interactions, remained uncertain. Characterization of the cytochrome P450 isoforms responsible for the metabolism(s) of drugs and herbal constituents is important for the identification of potential drug-drug or drug-herb interactions. The present study investigated the effects of Danshen on the metabolism of probe substrates of specific CYP isoforms including CYP1A2, CYP3A and CYP2C9, the isoforms that are responsible for the metabolism of warfarin to assess the potential interactions of Danshen with drugs that utilize these isoforms for their biotransformation.;Secondly, the effects of Danshen and its tanshinone components on CYP3A activity were investigated in vitro and in vivo in the rat. Formulated Danshen extract, the ethanolic extract from Danshen root, and tanshinones inhibited testosterone 6beta-hydroxylation (CYP3A) activity in vitro. Enzyme kinetic studies showed that tanshinone I, tanshinone IIA, and cryptotanshinone were competitive CYP3A inhibitors, whereas dihydrotanshinone was a noncompetitive CYP3A inhibitor. In vivo studies showed the pretreatments of formulated Danshen extract did not significantly change the pharmacokinetics of midazolam.;Thirdly, the effects of Danshen and its tanshinone components on CYP2C11 activity were investigated in vitro and in vivo in the rat. Formulated Danshen extract, the ethanolic extract from Danshen root, and tanshinones inhibited testosterone 2alpha-hydroxylation (CYP2C11) activity in vitro. Enzyme kinetic studies showed that tanshinone I, tanshinone IIA, cryptotanshinone, and dihydrotanshinone were competitive CYP2C11 inhibitors. Sub-chronic pretreatment of formulated Danshen extract increased the AUC, T1/2 but decreased CL of tolbutamide. These results suggested that Danshen inhibited the CYP2C activity in the rat. In conclusion, these results confirmed the possible mechanism is enzyme inhibition, involved in the interaction of Danshen and warfarin previously observed in rats.;The effects of Danshen and its tanshinones on human CYP1A2 (phenacetin O-deethylation), CYP3A4 (testosterone 6beta-hydroxylation), and CYP2C9 (tolbutamide 4-hydroxylation) activities were also investigated in vitro using pooled human liver microsomes and human CYP isoforms. The ethanolic fraction of Danshen root was more effective than water-soluble fraction in inhibiting human CYP1A2, CYP3A4 and CYP2C9 activities. Enzyme kinetic studies showed that tanshinone I, tanshinone IIA, and cryptotanshinone were competitive inhibitors of CYP1A2, CYP3A4 and CYP2C9 with varying effectiveness. Dihydrotanshinone was not a competitive inhibitor of CYP1A2 and CYP2C9, but a noncompetitive CYP3A4 inhibitor. CYP1A2 was most affected and CYP3A4 was least affected by Danshen and tanshinones. Compared with the results obtained from rat and human, rat is a good animal model for predicting Danshen-drug interactions in humans, especially drugs which are substrates of CYP1A2.;Firstly, the effects of Danshen and its tanshinone components on CYP1A2 activity were investigated in vitro and in vivo in the rat. Formulated Danshen extract, the ethanolic extract and the aqueous extract from Danshen root, and individual tanshinones inhibited phenacetin O-deethylation (CYP1A2) activity in vitro. Enzyme kinetic studies showed that tanshinone I, tanshinone IIA, cryptotanshinone, and dihydrotanshinone were competitive CYP1A2 inhibitors. Acute, sub-chronic and chronic pretreatments of formulated Danshen extract decreased the clearance (CL) of caffeine, with a concomitant increase in the area under concentration-time curve (AUC), and prolongation of the plasma half-life (T 1/2). These results suggested that Danshen inhibited rat CYP1A2 activity and altered the pharmacokinetics of the CYP1A2 probe substrates in vivo.;In conclusion, these results confirmed that Danshen-inhibited CYP activity, especially CYP1A2, then CYP2C9/11 (CYP2C9 in human, CYP2C11 in rats) in vitro. In vivo studies confirmed the clearance of the probe substrates was also decreased when co-administered with Danshen. Given that CYP1A2, CYP2C9 and CYP3A4 are responsible for the metabolism and disposition of a large number of drugs currently used in man, the concomitant use of Danshen with drugs which are substrates of CYP1A2, 2C9 and 3A4, especially CYP1A2, must be met with great caution.
机译：丹参，丹参干根，是一种在中国药典中列出的用于治疗心血管和脑血管疾病的草药。在临床前研究中，据报道丹参具有抗血小板，心脏保护，抗炎，保肝和抗HIV作用。然而，在患者同时使用丹参和华法林的过程中也观察到了夸大的抗凝和出血并发症，尽管中草药-药物相互作用，药效和/或药代动力学相互作用的机制仍然不确定。负责药物和草药成分新陈代谢的细胞色素P450亚型的表征对于鉴定潜在的药物-药物相互作用或药物-药物相互作用至关重要。本研究调查了丹参对特定CYP亚型包括CYP1A2，CYP3A和CYP2C9的探针底物代谢的影响，这些CYP亚型负责华法林的代谢，以评估丹参与利用这些同工型为其药物的药物之间的潜在相互作用其次，在大鼠体内和体外研究了丹参及其丹参酮成分对CYP3A活性的影响。配制丹参提取物，丹参根中的乙醇提取物和丹参酮在体外抑制睾丸激素6β-羟基化（CYP3A）活性。酶动力学研究表明，丹参酮I，丹参酮IIA和隐丹参酮是竞争性CYP3A抑制剂，而二氢丹参酮是非竞争性CYP3A抑制剂。体内研究显示丹参提取物的预处理对咪达唑仑的药代动力学没有明显改变。第三，在大鼠体内和体外研究了丹参及其丹参酮成分对CYP2C11活性的影响。配制丹参提取物，丹参根中的乙醇提取物和丹参酮在体外抑制睾丸激素2α-羟基化（CYP2C11）活性。酶动力学研究表明，丹参酮I，丹参酮IIA，隐丹参酮和二氢丹参酮是竞争性CYP2C11抑制剂。配制丹参提取物的亚慢性预处理可提高甲苯磺丁酰胺的AUC，T1 / 2但降低CL。这些结果表明丹参能抑制大鼠的CYP2C活性。总之，这些结果证实了可能的机制是酶抑制，参与了先前在大鼠中观察到的丹参与华法林的相互作用。;丹参及其丹参酮对人CYP1A2（非那西汀O-去乙基化），CYP3A4（睾酮6β-羟基化）的影响）和CYP2C9（甲苯磺丁酰胺4-羟基化）活性也进行了体外研究，使用了合并的人肝微粒体和人CYP亚型。丹参根的乙醇部分在抑制人CYP1A2，CYP3A4和CYP2C9活性方面比水溶性部分更有效。酶动力学研究表明，丹参酮I，丹参酮IIA和隐丹参酮是CYP1A2，CYP3A4和CYP2C9的竞争性抑制剂，但疗效不同。二氢丹参酮不是CYP1A2和CYP2C9的竞争性抑制剂，而是非竞争性CYP3A4抑制剂。丹参和丹参酮对CYP1A2的影响最大，对CYP3A4的影响最小。与从大鼠和人获得的结果相比，大鼠是预测人中丹参-药物相互作用的良好动物模型，尤其是作为CYP1A2底物的药物。首先，研究了丹参及其丹参酮成分对CYP1A2活性的影响。大鼠体内和体外。配制丹参提取物，丹参根的乙醇提取物和水提取物，以及单独的丹参酮在体外均抑制非那西丁的O-去乙基化（CYP1A2）活性。酶动力学研究表明，丹参酮I，丹参酮IIA，隐丹参酮和二氢丹参酮是竞争性CYP1A2抑制剂。配制的丹参提取物的急性，亚慢性和慢性预处理降低了咖啡因的清除率（CL），同时浓度-时间曲线（AUC）下的面积增加，血浆半衰期延长（T 1/2） ）。这些结果提示丹参能抑制大鼠CYP1A2的活性并改变体内CYP1A2探针底物的药代动力学;总而言之，这些结果证实了丹参能抑制CYP活性，特别是CYP1A2，然后是CYP2C9 / 11（人体内的CYP2C9，CYP2C11 ） 体外。体内研究证实，与丹参合用时，探针底物的清除率也降低了。鉴于CYP1A2，CYP2C9和CYP3A4负责目前人类中使用的大量药物的代谢和处置，因此丹参与以CYP1A2、2C9和3A4（尤其是CYP1A2）为底物的药物并用警告。

著录项

  • 作者

    Wang, Xin.;

  • 作者单位

    The Chinese University of Hong Kong (Hong Kong).;

  • 授予单位 The Chinese University of Hong Kong (Hong Kong).;
  • 学科 Health Sciences Toxicology.;Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 302 p.
  • 总页数 302
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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