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An integrative systems approach to predict herb-drug interactions quantitatively.

机译：一种集成系统方法，可定量预测草药-药物相互作用。

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摘要

Consumers often supplement their drug regimens with alternative therapies, including herbal products. Despite this widespread practice, reliable information to determine the risk or safety of herb-drug interactions is lacking. Assessing herb-drug interaction risk is challenging due to the complex composition of herbal products and relative dearth of knowledge of individual constituents that perpetrate these interactions. An integrated in vitro-in silico-in vivo approach involving human-derived in vitro systems, static and dynamic modeling, and proof-of-concept clinical studies provides a mechanistic framework to address these challenges.;Herbal products consist of multiple constituents that can alter drug disposition by multiple mechanisms. Inhibition of intestinal UDP-glucuronosyl transferases (UGTs) represents one potential mechanism that has not been investigated systematically. High-throughput screening of a small library of herbal product constituents identified multiple inhibitors of intestinal UGT1As. Silibinin, a semi-purified milk thistle extract, was selected as an exemplar herbal product to extend upon these results using the clinically relevant intestinal UGT1A victim drug, raloxifene. Incorporation of inhibition kinetics into a mechanistic static model suggested moderate clinical interaction risk. Physiologically-based pharmacokinetic (PBPK) models were developed to predict the clinical pharmacokinetic consequences of the silibinin-raloxifene interaction and inform design of a proof-of-concept clinical study. Clinical evaluation involving healthy volunteers substantiated model predictions and suggested low interaction risk of silibinin administered with raloxifene.;The objective of this dissertation was to evaluate the application of a quantitative framework to assess the risk of an herb-drug interaction mediated via a mechanism not previously investigated in humans. This objective was accomplished by recovering in vitro kinetic and binding parameters associated with the silibinin-raloxifene interaction, expanding a PBPK silibinin-drug interaction model by incorporating the recovered parameters, and conducting a proof-of-concept clinical study to evaluate model predictions. Although outlined in the specific context of the silibinin-raloxifene interaction, the principles underlying these approaches can be applied to the study of a multitude of herb-drug interactions. Ultimately, these integrative approaches can be used to establish paradigms for the prospective evaluation of herb-drug interaction potential that will provide information to promote safe, evidence-based use of herbal products in combination with conventional medications.
机译：消费者经常用包括草药产品在内的替代疗法来补充他们的药物疗法。尽管有这种广泛的实践，但是缺乏确定草药-药物相互作用的风险或安全性的可靠信息。由于草药产品的复杂组成以及导致这些相互作用的个别成分的知识相对匮乏，评估草药与药物相互作用的风险具有挑战性。一种集成的体外-体外-硅胶-体内方法，涉及人类衍生的体外系统，静态和动态建模以及概念验证的临床研究，为应对这些挑战提供了一种机械框架。草药产品由多种成分组成，这些成分可以通过多种机制改变药物处置。抑制肠道UDP-葡萄糖醛酸转移酶（UGTs）代表了一种尚未被系统研究的潜在机制。对草药产品成分的小型文库的高通量筛选确定了肠道UGT1As的多种抑制剂。水飞蓟宾是一种半纯化的乳蓟提取物，被选作一种典型的草药产品，以使用临床相关的肠道UGT1A受害者药物雷洛昔芬来扩展这些结果。将抑制动力学纳入机械静态模型表明中等程度的临床相互作用风险。开发了基于生理的药代动力学（PBPK）模型，以预测水飞蓟宾-雷洛昔芬相互作用的临床药代动力学后果，并为概念验证临床研究的设计提供依据。涉及健康志愿者的临床评估证实了模型的预测，并表明雷洛昔芬与水飞蓟宾的相互作用风险较低。本论文的目的是评估定量框架在评估药物-药物相互作用风险中的应用，该风险是通过以前未曾有过的机制介导的在人类中进行了调查。通过恢复与水飞蓟宾-雷洛昔芬相互作用相关的体外动力学和结合参数，通过结合所恢复的参数扩展PBPK水飞蓟宾-药物相互作用模型，并进行概念验证性临床研究以评估模型预测，可以实现该目标。尽管在水飞蓟宾-雷洛昔芬相互作用的特定背景下进行了概述，但这些方法所基于的原理仍可用于多种草药-药物相互作用的研究。最终，这些综合方法可用于建立对草药与药物相互作用潜力进行前瞻性评估的范例，这些范例将提供信息，以促进与传统药物联合安全，循证使用草药产品。

著录项

  • 作者

    Gufford, Brandon Tyler.;

  • 作者单位

    Washington State University.;

  • 授予单位 Washington State University.;
  • 学科 Pharmaceutical sciences.
  • 学位 Ph.D.
  • 年度 2015
  • 页码 244 p.
  • 总页数 244
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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