KINETICS AND CLINICAL IMPORTANCE OF DISPLACEMENT OF WARFARIN FROM ALBUMIN BY ACIDIC DRUGS *

Displacement of protein-bound drugs from their binding sites on plasma proteins increases their concentration in the free active form.' An increase in the concentration of the free form of such drugs enhances their pharmacologic effect. Displacement from plasma proteins is particularly important in the case of highly protein-bound drugs with a small margin of safety. In patients treated with warfarin or other highly bound coumarin derivatives, increased levels of unbound anticoagulant may lead to excessive hypoprothrombinemia and bleeding.2B3 Identification of drugs that can displace coumarin anticoagulants from their binding sites on plasma albumin may prevent serious clinical mishaps. Once the displacing potential of such agents is established, one can anticipate the need for a reduction in warfarin dosage when they are added to therapy. In the usual clinical situation, detection of drugs that potentiate or reduce the hypoprothrombinemic action of warfarin may be difficult and longdelayed. Often many drugs are given concomitantly, clinical factors that influence the level of vitamin K-sensitive clotting proteins are continually changing, and the dose of warfarin may be altered daily. Fortunately, drugs that displace warfarin from albumin and could thereby potentiate its hypoprothrombinemic action can be identified by in uitm studies. The clinical importance of this displacement and the degree of potentiation can then be established by controlled experiments in volunteers and through prospective monitoring of hospitalized anticoagulated patients. Warfarin is an acidic drug with a pK, of 4.8 that may be considered bound a t 2.6 binding sites on human albumin each with an association constant of 230,000 M-' a t 2 7 O C.' Other drugs may directly compete with warfarin for the sites of binding (competitive interference) or may indirectly alter the affinity or number of warfarin-binding sites by binding a t other sites on albumin (noncompetitive interference) .586 Drugs most likely to displace warfarin are acidic compounds that are highly bound to albumin and reach high plasma levels during clinical use (TABLE 1). Fhenylbutazone, a potent competitive displacer of warfarin, is an acidic compound that is over 99% bound to human albumin and can reach plasma concentrations exceeding 200 mg/l during its therapeutic use."