Herb-Drug Glucuronidation Interactions

描述(申请人提供)：数以百万计的美国人使用草药补充剂来促进他们的健康和健康，其中许多与处方药相结合。因此，由于细胞色素P450酶和/或外排转运蛋白P-糖蛋白的诱导或抑制而导致的严重的药物-药物相互作用已有报道。然而，关于草药补充剂与通过尿苷二磷酸葡萄糖醛酸基转移酶(UGT)酶进行结合代谢的药物相互作用的潜力，我们的循证知识存在差距。我们的实验室最近发现了强烈抑制UGT介导的代谢的草药补充剂。基于这些数据，这项应用的目标是确定常用草药补充剂可以在多大程度上抑制人类的UGT酶。中心假设是，服用草药补充剂会改变一种主要由UGT介导的代谢消除的药物的药代动力学。本项目的目标是在健康志愿者中确定：1)长期服用银杏叶对霉酚酸药代动力学的影响；2)绿茶提取物对雷洛昔芬药代动力学的影响。这些药物代表了两种最畅销的药物，其中葡萄糖醛酸化作用是主要的消除途径；每种药物的血药浓度增加都可能产生可怕的后果。了解草药补充剂如何影响UGT介导的药物代谢对人类健康很重要，因为这将填补知识的重大空白。这项翻译研究将提供有关选定草药补充剂在多大程度上改变霉酚酸和雷洛昔芬这两种临床上重要的UGT底物的处置的关键信息。 公共卫生相关性：草药与药物的相互作用仍然是一个重大的公共卫生问题，草药补充剂的使用率很高。提出的这项研究意义重大，因为它有望提供关于草药-药物葡萄糖醛酸化相互作用的潜在的循证知识，这最终将帮助卫生保健提供者预测潜在的草药-药物相互作用，并有助于合理调整治疗管理。

DESCRIPTION (provided by applicant): Millions of Americans use herbal supplements to promote their health and wellness, many of them in combination with prescription medications. Accordingly, serious adverse herb- drug interactions resulting from the induction or inhibition of cytochrome P450 enzymes and/or the efflux transporter P-glycoprotein have been reported. However, there is a gap in our evidence-based knowledge regarding the potential of herbal supplements to interact with medications that undergo conjugative metabolism by uridine diphosphate glucuronosyl transferase (UGT) enzymes. Our laboratory has recently identified herbal supplements that strongly inhibit UGT-mediated metabolism. Based on these data, the objective of this application is to determine the extent to which commonly used herbal supplements can inhibit UGT enzymes in humans. The central hypothesis is that taking herbal supplements will alter the pharmacokinetics of a drug eliminated predominately by UGT-mediated metabolism. The goals of this project are to determine in healthy volunteers: 1) the effect of prolonged Ginkgo biloba administration on mycophenolic acid pharmacokinetics; and 2) the effect of green tea leaf extract administration on raloxifene pharmacokinetics. These drugs represent two of the top selling medications for which glucuronidation is the primary route of elimination; increased blood concentrations for each of these drugs can have dire consequences. It is important for human health to understand how herbal supplements influence the UGT-mediated metabolism of medications, as this will fill a significant gap in knowledge. This translational research will provide critical information on the extent to which selected herbal supplements alter the disposition of mycophenolic acid and raloxifene, two clinically important UGT substrates. PUBLIC HEALTH RELEVANCE: Herb-drug interactions continue to be a significant public health concern and the prevalence of herbal supplement use is substantial. The research proposed is significant because it is expected to provide evidence-based knowledge on the potential for herb-drug glucuronidation interactions, which will ultimately help health care providers anticipate potential herb-drug interactions and contribute to rational adjustments in therapy management.