• DOI:10.1345/aph.1A208
• Corpus ID: 20855578

Revisiting the Significance of Warfarin Protein-Binding Displacement Interactions

@article{Sands2002RevisitingTS,
  title={Revisiting the Significance of Warfarin Protein-Binding Displacement Interactions},
  author={Charles D. Sands and Edwina S Chan and Timothy E. Welty},
  journal={Annals of Pharmacotherapy},
  year={2002},
  volume={36},
  pages={1642 - 1644}
}

• C. Sands, E. Chan, T. Welty
• Published 1 October 2002
• Medicine
• Annals of Pharmacotherapy

Most clinicians who manage patients on warfarin therapy are aware of the transient nature of changes in the prothrombin time (PT) secondary to protein-binding displacement interactions. However, anecdotal case reports and clinical impressions by some healthcare professionals continue to inflate, on occasion, the importance of warfarin protein-binding displacement interactions,1 despite the fact that the transient nature of the interaction has been well described for >30 years.2-7 Thus, it is timely and important to revisit the pharmacokinetic explanation for the relative lack of clinical significance of these interactions. Three proteins in human plasma account for the binding of most drugs: albumin, α1-acid glycoprotein, and lipoproteins.8 Racemic warfarin is approximately 99% bound to plasma proteins, primarily to albumin.9 The addition of other highly protein-bound drugs to a warfarin drug regimen may result in changes of the binding characteristics of either drug. Protein-binding displacement of warfarin will result in an increase in the unbound (free) fraction (fu), which may or may not affect the pharmacodynamic response.9 Chan1 has suggested that the clinical significance of protein-binding displacement in warfarin drug interactions has been overstated. Many drugs can displace warfarin from plasma albumin-binding sites with a resultant increase in the pharmacologically active unbound drug concentration. What many clinicians forget, however, is that plasma is an open compartment and the increase in unbound drug redistributes not only to warfarin receptor sites in the tissue, but also to sites of metabolism.10 Thus a new steady-state is achieved, with the unbound drug concentration returning to its predisplacement concentration.11 Therefore, the transient increase in the warfarin fraction may or may not elicit a significant pharmacodynamic response (increased PT).9 In our experience in a large anticoagulation clinic in a major medical center (University of Alabama at Birmingham Medical Center, The Kirklin Clinic; average of 250 pts./wk), major problems have been infrequent when protein-binding displacement drugs have been added to a patient’s warfarin regimen. The displacement may be clinically significant in a patient on chronic warfarin therapy only at the time the displacing drug is either added or withdrawn. In these situations, the effect will be transient and a CSS should be reached in 7–10 days.1 In explaining this phenomenon to residents and clerkship students rotating through the anticoagulation clinic, we have successfully used the following pharmacokinetic reasoning process (largely adapted from Bauer12). The concept of drug clearance (Cl) from the body is important to the understanding of the protein-binding displacment/warfarin interaction. Because Cl determines the average Css,avg for a given rate of drug administration (k0). Css,avg = k0 / Cl Eq. 1