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Protein Binding of Coumarin Anticoagulants in Disease States

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Abstract

Excessive hypoprothrombinaemia accompanying the use of coumarin oral anticoagulants may be associated with changes in coumarin disposition which, in turn, can arise from changes in coumarin plasma protein binding. Coumarins bind extensively to human serum albumin with primary binding affinity constants of approximately 105 L/mole. The nature of coumarin-albumin binding is chiefly hydrophobic although hydrogen bonding and electrostatic interactions are also involved. Differences in analytical techniques and conditions have given rise to varied values for numbers of binding sites, binding affinity constants, and extent of albumin, serum, or plasma binding. However, the extent of coumarin binding appears to hold relatively constant over expected therapeutic concentration ranges. The plasma binding of warfarin is characterised by marked interindividual differences.

Apparent volumes of distribution of coumarins approximate the size of the albumin space and are apparently dose independent with the exception perhaps of dicoumarol (bishydroxycoumarin) which has been reported to exhibit a decreasing apparent volume of distribution with increasing dose. Volumes of distribution increase as the free coumarin fraction increases. Plasma albumin serves as a storage depot for coumarins, and their hepatic elimination is restrictive; that is, limited to the free fraction perfusing the liver. Increases in the free fraction of coumarins will be accompanied by increased clearance rates, and changes in hepatic blood flow rates will have negligible effects on coumarin half lives.

Conditions which may be associated with diminished coumarin binding to albumin and enhanced elimination include: thyrotoxicosis, hyperbilirubinaemia, fasting, stress, diabetes mellitus, acute myocardial infarction, cirrhosis, hepatic tumours, and renal dysfunction. However, the only pathological condition in man which is clearly accompanied by decreases in coumarin plasma binding, is renal dysfunction. The cause of diminished warfarin binding in patients with renal dysfunction has not been elucidated, although the presence of an endogenous warfarin-binding inhibitor seems likely.

It is not clear whether conditions leading to increases in coumarin free fractions require adjustments in coumarin dosage schedules. Theoretical considerations suggest that neither increased disbribution volumes nor clearance rates associated with increasing the free coumarin fraction will lead to changes in the average steady slate plasma levels of free drug. A preliminary study in patients with renal dysfunction suggests that warfarin dosage regimens do not require adjustment in such patients. However, increases in the coumarin free fraction, apparent volume of distribution, and clearance rate may be attended by increases in peak unbound coumarin levels and decreased trough levels of unbound coumarin thereby making anticoagulant control more difficult. Ultimately, these possibilities must be confirmed or rejected on the basis of additional clinical investigations.

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  1. The Medical College of Ohio, The University of Toledo College of Pharmacy and The Department of Medicine, Toledo, Ohio, USA

    Kenneth Bachmann (Assistant Professor of Pharmacology) & R. Shapiro

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Bachmann, K., Shapiro, R. Protein Binding of Coumarin Anticoagulants in Disease States. Clin Pharmacokinet 2, 110–126 (1977). https://doi.org/10.2165/00003088-197702020-00003

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