The Editorial Executive Committee welcomes letters, which should be less than 250 words. Before a decision to publish is made, letters which refer to a published article may be sent to the author for a response. Any letter may be sent to an expert for comment. When letters are published, they are usually accompanied in the same issue by their responses or comments. The Committee screens out discourteous, inaccurate or libellous statements. The letters are sub-edited before publication. Authors are required to declare any conflicts of interest. The Committee's decision on publication is final.

Letter to the Editor

Editor, – The 'Medicinal mishap' about the fenofibrate-warfarin interaction (Aust Prescr 2006;29:166) perpetuates the myth that protein binding interactions are clinically relevant. Unless the clearance of unbound drug is saturable (not the case with fenofibrate), protein binding displacement interactions do not lead to sustained increases in steady-state concentrations of unbound drug if the drug has a low clearance (as is the case with warfarin).1,2 It is the unbound concentrations of drug that correlate with the pharmacological effect. The only determinant of steady-state unbound concentration of drug, apart from the dose rate, is its clearance. This is generally dependent on hepatic metabolism or, in some cases, renal clearance or a combination of both.

Fenofibrate is an analogue of clofibrate, so information about clofibrate is relevant to the fenofibrate-warfarin interaction. Clofibrate potentiates the anticoagulant activity of warfarin but not because of displacement from plasma proteins. It causes a very small increase in the free fraction of warfarin but 'this pharmacokinetic interaction does not account for the clinical interaction between the two drugs, since free warfarin concentrations are unchanged'.3The mechanism of the interaction is unknown but is likely to be related to warfarin's effect on the synthesis of clotting factors. The metabolism of clofibrate is also a significant consideration. Clofibrate is hydrolysed to the active metabolite, clofibric acid, which is largely metabolised to its ester glucuronide. In a process known as 'futile cycling', ester glucuronides of clofibric acid and several other active drugs are retained in renal impairment. Their resultant hydrolysis yields higher than average plasma concentrations of the active drug. This futile cycling in renal failure with marked retention of clofibric acid has been reported in animal studies.4

The patient in the case had a very low creatinine clearance (17 mL/min). We suggest that there was 'futile cycling' of fenofibric acid, the active metabolite of fenofibrate, leading to high plasma concentrations and a substantial interaction with warfarin. Five other cases of a marked potentiation of warfarin by fenofibrate have been reported.5,6 Unfortunately, the patients' renal function was not recorded but three were elderly with multiple diseases so they may have had substantial renal impairment.

The important point is that protein binding displacement interactions between any pair of highly bound drugs do not alter their unbound concentrations and, consequently, increased effects are most unlikely. This applies particularly to drugs with low clearances, such as warfarin.

We agree with the advice that closer monitoring of patients on warfarin is needed when starting fenofibrate to avoid excessive anticoagulation. Particular care is necessary if the patient has renal impairment.

Richard O Day
Professor of Clinical Pharmacology
University of New South Wales and St Vincent's Hospital

Garry Graham
Visiting Professor, Faculty of Medicine
University of New South Wales

Ken Williams
Associate Professor, Faculty of Medicine
University of New South Wales and St Vincent's Hospital

Author's comments

Dr RA Ghiculescu, author of the case, comments:

I concur that protein binding is usually of little clinical importance. Many so-called protein binding displacement interactions are reported but the weight of evidence shows this is not the mechanism to explain clinically relevant drug interactions. However, the reference I cited does report such a phenomenon with fenofibrate itself and was therefore quoted as one of two possible mechanisms for this interaction. Apart from protein binding displacement the other mechanism was the probable inhibition of the CYP450 2C9 by fenofibrate.7


  1. Interacting drugs. In: Clinical pharmacokinetics: concepts and applications. 3rd ed. Rowland M, Tozer TN. Baltimore: Lippincott Williams & Wilkins; 1995. p. 267-89 .
  2. Sjoqvist E, Borga O, Dahl M-L, ormen ML. Fundamentals of clinical pharmacology. In: Speight TM, Holford NH. Avery's drug treatment: a guide to the properties, therapeutic use and economic value of drugs in disease management. 4th ed. Auckland: Adis International; 1997. p. 1-73.
  3. Bjornsson TD, Meffin PJ, Swezey S, Blaschke TF. Clofibrate displaces warfarin from plasma proteins in man: an example of a pure displacement interaction. J Pharmacol Exp Ther 1979;210:316-21.
  4. Meffin PJ, Zilm DM, Veenendaal JR. Reduced clofibric acid clearance in renal dysfunction is due to a futile cycle. J Pharmacol Exp Ther 1983;227:732-8.
  5. Ascah KJ, Rock GA, Wells PS. Interaction between fenofibrate and warfarin. Ann Pharmacother 1998;32:765-8.
  6. Kim KY, Mancano MA. Fenofibrate potentiates warfarin effects. Ann Pharmacother 2003;37:212-5.
  7. Kim KY, Mancano MA. Fenofibrate potentiates warfarin effects. Ann Pharmacother 2003;37:212-5.