Dicumarol Labelled with C14.

Lee, C. C.; Trevoy, L. W.; Spinks, J. W. T.; Jaques, L. B.

doi:10.3181/00379727-74-17838

Cited by 31 publications

(3 citation statements)

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“…These reports suggest that the antidotal action of vitamin K on the prothrombinopenic effect of the coumarin anticoagulant drugs is not mediated through an alteration in the pharmacodynamics of the anticoagulant. The antidotal effect of vitamin K in animals given Dicumarol was attributed by Lee, Trevov, Spinks, and Jaques (25) to direct displacement of the drug from the liver. These results could not be confirmed, however, by Green, Sondergaard, and Dam (26).…”

Section: Discussionmentioning

confidence: 98%

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

O’Reilly¹,

Aggeler²,

Leong³

1963

J. Clin. Invest.

201

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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 Their methods, however, were unpublished except as doctoral theses, or were not readily adaptable for studies in man.Recently, we described a spectrophotometric method for the estimation of warfarin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.

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Section: Discussionmentioning

confidence: 98%

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

O’Reilly¹,

Aggeler²,

Leong³

1963

J. Clin. Invest.

201

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“…

The distribution and elimination of dicoumarol in animals have already been studied by several investigators (e. g. WEINER et al 1950;LEE et al 1950; HAUSNER et al 1951 ;GREEN et al 1956). The spectrophotometric methods and the tracer methods, as used for determining dicoumarol in these investigations, are not entirely specific for the drug and metabolites may interfere with its determination.

…”

mentioning

confidence: 99%

Studies on the Fate of Intravenous Dicoumarol in the Rat

Christensen

1964

Acta Pharmacologica et Toxicologica

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The distribution and elimination of dicoumarol in animals have already been studied by several investigators (e. g. WEINER et al. 1950;LEE et al. 1950; HAUSNER et al. 1951 ;GREEN et al. 1956). The spectrophotometric methods and the tracer methods, as used for determining dicoumarol in these investigations, are not entirely specific for the drug and metabolites may interfere with its determination. A new paper chromatographic method for determining dicoumarol (CHRISTENSEN 1964) is apparently more specific than those mentioned above, and a study of the distribution and elimination of dicoumarol in rats has been made by this method. Experimental methodsWhite female rats weighing about 190 g were fed on a commercial chicken diet. Dicoumarol (5.2 mg) dissolved in 0.1 M-NaOH was slowly injected into the tail vein of each rat at the beginning of the experiment. The solution contained 10 mg of dicoumarol per ml and was prepared immediately before use. The rats were then placed, with free access to water and food, in metabolic cages for the collection of urine and faeces. At various times (one to forty-eight hours) after the injection of dicoumarol the animals were killed by heart puncture under ether anaesthesia, and as much blood as possible was withdrawn to reduce the amount of blood remaining in the tissues. The organs to be analysed and the entire gastro-intestinal tract, with its contents, were removed and weighed. No attempt was made to separate the gastrointestinal tract proper from its content. Each rat was then skinned, and the skin, after depilation and weighing, was frozen in a bath of dry ice with absolute ethanol and crushed in a mortar; the carcass was minced in a meat mincer. The organs and tissues thus treated were then homogenised with 0.9% (w/v) sodium chloride in an Ultra-Turrax homogeniser. The homogenates as a rule contained 25-35% (w/v) of tissue. Homogenates of faeces were also prepared.

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“…Isotope studies by Spinks & Jaques (1950), Lee, Trevoy, Spinks & Jaques (1950) and Solvonuk, Jaques, Leddy, Trevoy & Spinks (1952) have provided information about the fate of dicoumarol and menaphthone in the body. Dicoumarol labelled with 14C in the methylene bridge was administered intravenously to mice and rabbits.…”

Section: Haemorrhagic Condition Due To Hypervitaminosis Amentioning

confidence: 99%

Recent Studies on Vitamin K

Dam¹

1953

Proc. Nutr. Soc.

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Dicumarol Labelled with C14.

Cited by 31 publications

References 0 publications

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

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

Studies on the Fate of Intravenous Dicoumarol in the Rat

Recent Studies on Vitamin K

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