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Drug Disposition and Drug–Drug Interactions: Importance of First-Pass Metabolism in Gut and Liver

  • Catherine K. Yeung
  • Ping Zhao
  • Danny D. Shen
  • Kenneth E. Thummel
Chapter

Abstract

Drugs with high intestinal and hepatic extraction that undergo biotransformation are often involved in significant metabolic drug–drug interactions when co-administered with enzyme inhibitors or inducers. These interactions can result in sub- or supra-therapeutic drug levels which can lead to major adverse events. We present an overview of clinically relevant examples of metabolically based, first-pass drug–drug interactions, as well as an introduction to the pharmacokinetic principles of sequential first-pass intestinal and hepatic metabolism. We conclude with pharmacokinetic simulations that illustrate the complex relationship between inhibitor-induced changes in organ intrinsic clearances and systemic drug exposure as a first step in the development of pharmacokinetic modeling techniques that will facilitate the prediction and avoidance of metabolically based drug–drug interactions.

Keywords

Drug Interaction Grapefruit Juice Intrinsic Clearance Mucosal Blood Flow Intestinal Metabolism 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Catherine K. Yeung
    • 1
  • Ping Zhao
    • 2
  • Danny D. Shen
    • 1
  • Kenneth E. Thummel
    • 3
  1. 1.Departments of PharmaceuticsUniversity of WashingtonSeattleUSA
  2. 2.Office of Clinical Pharmacology, Office of Translational SciencesCenter for Drug Evaluation and Research, Food and Drug AdministrationSilver SpringUSA
  3. 3.Departments of PharmaceuticsUniversity of WashingtonSeattleUSA

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