Studies on the Coumarin Anticoagulant Drugs: The Pharmacodynamics of Warfarin in Man*

Abstract

Link (1) suggested in 1948 that the coumarin compound warfarin be used as a rodenticide. Its first human use was in a suicide attempt in 1952 (2). Although warfarin has been employed increasingly in the treatment of thromboembolic disorders (3)(4)(5), no published reports of its physiologic disposition in man have appeared, probably owing largely to the lack of a suitable method for its measurement in biologic fluids (6).Weiner, Brodie, and Burns (7,8) stated that the half-life of warfarin in man is 90 hours, but did not include the assay method, or give supporting data. In 1953, Yuyama, Goto, and Umezu (9) described a colorimetric method for the estimation of warfarin in rat plasma, but apparently this method was never applied to man. Since 1954, several investigations of warfarin in the rat have appeared, including the studies of Garner (10), Eble (11), and Lin (12). Their methods, however, were unpublished except as doctoral theses, or were not readily adaptable for studies in man.Recently, we described a spectrophotometric method for the estimation of warfarin in biologic fluids (13), and have used this method in the present study to investigate the pharmiacodynamics of warfarin in man. We determined the concentrations of warfarin in the plasma and of a warfarin metabolite in the urine of normal subjects after both oral and intravenous administration of the drug. Analysis of the data provided information on its absorption, elimination, apparent volume of distribution, and excretion. Differences in its biologic effect were evaluated by simultaneous measurements of its plasma concentration and of prothrombin complex activity. * Work supported by U. S. Public Health Service grant H-2754. METHODSThe subjects, all volunteers, were 14 normal men and women, ages 27 to 63 years, and one patient, age 72 years, with coronary artery disease who was included because he was unusually resistant to the prothrombinopenic effects of the drug.Warfarin sodium 1 was administered either orally in the form of tablets (starch base) or by iv injection. The tablets were swallowed whole in the morning by subjects in the postabsorptive state, and no food was taken for at least 2 hours thereafter. For iv administration, lyophilized warfarin sodium was reconstituted in distilled water. The total dose was injected into the antecubital vein in less than 1 minute. The dose of warfarin given by either route was based on body weight in an attempt to equalize the effect of the drug on subjects with different plasma volumes, assumed to be a function of body weight. A standard dose of 1.5 mg per kg of body weight was selected so that drug levels and prothrombin complex responses would be in a clearly measurable range for several days after administration of warfarin.Test specimens were prepared as follows. Blood obtaimed by clean venipuncture was mixed in glass tubes in a proportion of 9: 1 with 3.2% sodium citrate in 0.7%c saline and centrifuged at 2,000 rpm for 20 minutes at 4°C.

Design evaluation and optimisation in multiple response nonlinear mixed effect models: PFIM 3.0

“…To do this, we use an example extracted from a classical pharmacology study published 40 years ago, by O'Reilly et al [26,27] on the pharmacokinetics and pharmacodynamics of 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 14 warfarin. Previously, these data have been fitted by Holford for the analysis of the dose-effect relationship of warfarin [28] using nonlinear mixed effects models.…”

“…We optimise and derive two population designs using the Fedorov-Wynn algorithm, either imposing the same sampling times across responses or not, and we compare them to an "empirical design" used in the previous study of warfarin [26,27]. Globally, the expected precision of estimations are in the same range for the three designs, even if the number of samples per patient, and thus, the total number of samples are considerably reduced (38% fewer samples in the optimised designs compare to the empirical one).…”

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

“…Countercurrent distribution analysis of plasma of patients receiving clinical doses of warfarin shows essentially only the unchanged drug and similar analysis of urine reveals only hydroxylated metabolites of warfarin (2,3). To determine if the absence of the metabolites in plasma and the absence of unchanged drug in the urine could be correlated with albumin binding, we also studied the four known metabolites by equilibrium dialysis.…”

Glucuronidation of Monohydroxylated Warfarin Metabolites by Human Liver Microsomes and Human Recombinant UDP-Glucuronosyltransferases

“…Both enantiomers inhibit the regeneration of reduced vitamin K by blocking vitamin K epoxide reductase complex, thereby reducing the formation of active clotting factors II, VII, IX, and X (Hirsh et al, 2001;Holbrook et al, 2005;Wajih et al, 2005;Rettie and Tai, 2006). It is readily absorbed, and peak systemic concentrations occur within 60 to 90 min (O'Reilly et al, 1963;Holford, 1986;Chan et al, 1994). Approximately 99% of warfarin is systemically bound to serum albumin.…”