Studies on the Coumarin Anticoagulant Drugs : A Comparison of the Pharmacodynamics of Dicumarol and Warfarin in Man

Abstract

SummaryThe pharmacodynamic and prothrombinopénie effects of the coumarin anticoagulant drugs warfarin and dicumarol were compared in man by means of specific chemical assays for the drugs and the Quick prothrombin time for the response. The absorption of warfarin was rapid and complete, and the prothrombinopénie response was similar after administration by any route. Absorption of dicumarol as a solution or powder was rapid while as whole tablets it was often slow. Dicumarol in solution taken orally produced higher maximum concentrations of drug in plasma, more rapid absorption rates, less unchanged drug in stool and an earlier and greater prothrombin complex response than the tablets. Only a slight effect was produced by varying the formulation of warfarin. In all subjects 15 to 30% of the oral dose of dicumarol was recovered as unchanged drug in the stool. Unchanged warfarin was not recovered from the stool in any experiment.The apparent volume of distribution (Vd) for warfarin and high doses of dicumarol was about 12.5% of body weight, approximately the size of the albumin space. The long half-time of disappearance (t½) of both drugs, their prolonged duration of action, small volume of distribution, and lack of excretion of unchanged drug in the urine are probably related to their high degree of binding to plasma proteins. The t½ and Vd for warfarin are independent of dose size; the unusual dependency of these parameters on dose size with dicumarol suggests tissue uptake, perhaps by the reticuloendothelial system.A good correlation was found between the t½ of warfarin and dicumarol and the magnitude and duration of response. Up to a certain point increasing the dose of these drugs hastened the occurrence of hypoprothrombinemia ; beyond a dose size characteristic for each individual no further hastening could be obtained.A substance extracted from the stool of subjects receiving dicumarol intravenously and orally is probably a metabolite of the drug.

Interaction of the anticoagulant drug warfarin and its metabolites with human plasma albumin

“…Because the albumin and warfarin molecules are hydrated on solution in aqueous solvent, there should be an increase in the number of molecular species on binding because of the release of water of solvation from both the warfarin and albumin molecules; hence, one would expect an increase in entropy for the interaction (25 The interaction of drugs with proteins represents an important aspect of drug metabolism because of the interactions with a) receptor proteins which may result in pharmacologic activity of the drug, b) an enzyme responsible for the degradation of the drug, and c) inert proteins of blood (albumin) or tissue which may be responsible for the distribution and transport of the drug and may limit its activity or metabolism (31). All three of these aspects of drug metabolism have been studied with warfarin in man: the first by the prothrombinopenic response (2), the second by the half-life of the drug in plasma and its correlation with the duration of the anticoagulant effect (32), and the third by the warfarin-albumin interaction described herein. Administration of the 6-, 7-, and 8-hydroxywarfarin metabolites to rats does not produce an anticoagulant effect (4).…”

Studies on the Coumarin Anticoagulant Drugs: Interaction of Human Plasma Albumin and Warfarin Sodium*

“…The therapeutic action of a drug often depends on its effective concentration, as well as on its intrinsic activity (32). The effective concentration is the concentration of free drug, which for warfarin in human plasma and in 5% human plasma albumin is less than 5%o of the total warfarin present (33). Binding to plasma albumin probably affects the duration and intensity of a drug's action and protects the body against the full pharmacologic effect of the drug by temporarily inactivating it in a circulating reservoir that is in equilibrium with the unbound, active form of the drug (7,32).…”

“…Thus, the primary effect of the warfarin-albumin interaction would be the confining of the drug molecules within the vascular space in an inactive form, thereby hindering their access to the sites of drug action, excretion, and metabolism (14). The strength of this binding process would explain why warfarin sodium does not enter red blood cells or cerebral spinal fluid, does not appear in the urine, and has a small volume of distribution that is identical to the albumin space (33). The long half-life of warfarin in plasma and the long biologic effect are consistent with such a strong interaction (1).…”

Poly(fumaric-co-sebacic) microspheres as oral drug delivery systems

“…Our theory was that bioavailability of the drug could be improved by using a bioadhesive delivery vehicle to place the drug in close contact with the mucosal epithelium. When given orally, dicumarol is taken up mainly in the small intestine, and its absorption is rate-limited by the dissolution kinetics (O'Reilly et al, 1964) of the poorly soluble weak acid. The plasma half-life of the drug in rats is approximately 6 h when administered at an oral dose of 20 mgkg (Tembo and Bates, 1974).…”