Pharmacokinetic Study of the Digoxin-acenocoumarol Interaction in Rabbits

Abstract

Digoxin remains among the most frequently administered cardiac drugs. Its narrow therapeutic range, together with the existence of many factors that modify the pharmacological response to digoxin, make routine monitoring of its plasma levels crucial. Among such factors, one of the most important is the large number of interactions shown by the drug, most of them with a pharmacokinetic basis. 1,2) Acenocoumarol is the oral anticoagulant most widely used in continental Europe. Despite its widespread use, the literature contains few references to this drug, particularly in comparison with the large body of information on warfarin, the most widely used anticoagulant in other areas of the world. The important pharmacokinetic differences shown by acenocoumarol mean that the results obtained with other anticoagulants cannot be extrapolated to this drug. [3][4][5] Treatments with digoxin and acenocoumarol are usually chronic and often simultaneous. At two hospitals in our region it was observed that patients receiving treatment with acenocoumarol required higher doses of digoxin to control their conditions and for digoxin levels within the therapeutic range to be obtained.6) The literature contains no references to this possible interaction. Indeed, in a review paper on the interactions of anticoagulants Harder and Thürmann 7) specifically cite the absence of references to interactions between cardiotonic glucosides and coumarin derivatives, and they highlight the need for controlled studies of these drugs. Accordingly, the aim of the present work was to evaluate the potential pharmacokinetic interaction between digoxin and acenocoumarol in rabbits both in vitro and in vivo. MATERIALS AND METHODSThe interaction between digoxin and acenocoumarol was studied in in vitro and in vivo experiments. In the in vitro studies, the binding of digoxin to cardiac tissue homogenates was assessed in the presence and absence of acenocoumarol, using the equilibrium dialysis technique. In the in vivo experiments, the kinetics of digoxin administered in single-and multiple-dose regimens were compared in a group of control rabbits and in another group treated with both drugs simultaneously. The levels of digoxin in heart tissue at the end of the dosage regimen were also studied.In Vitro Study The in vitro studies of the binding of digoxin to heart homogenates were carried out using the equilibrium dialysis technique. 8,9) Heart Tissue Homogenates: Homogenates were prepared from rabbit hearts at a concentration of 50 mg/ml in phosphate buffer (1/15 M, pH 7.4) to study the binding of digoxin to heart tissue. Untreated homogenates and homogenates previously treated with a solution of acenocoumarol (1 mg/ml) over 4 h before the dialysis experiments were compared.Prior to the study, experiments had been conducted that showed that digoxin is not adsorbed onto the dialysis membrane. Neither was any significant shift across the membrane observed. The process was carried out at physiological temperature (37°C). Using this technique, two types of ex...