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Studies on the Coumarin Anticoagulant Drugs : The Assay of Warfarin and its Biologic Application[*]
Robert A. O’Reilly
1
Hematology Research Laboratory, Children’s Hospital, and the Department of Medicine, University of California School of Medicine, San Francisco, California
,
Paul M. Aggeler
1
Hematology Research Laboratory, Children’s Hospital, and the Department of Medicine, University of California School of Medicine, San Francisco, California
,
M Silvija Hoag
1
Hematology Research Laboratory, Children’s Hospital, and the Department of Medicine, University of California School of Medicine, San Francisco, California
,
Lois Leong
1
Hematology Research Laboratory, Children’s Hospital, and the Department of Medicine, University of California School of Medicine, San Francisco, California
A spectrophotometric method is described for the determination of warfarin in biologic fluids. The warfarin is extracted from the specimen with acidified ethylene dichloride, washed with mild alkali and recovered from the organic phase with strong alkali. The extinction is then measured spectrophotometri-cally at the ultraviolet absorption maximum for warfarin. Results of UV absorption spectrophotometry and countercurrent distribution analysis showed that the assay is specific for unchanged warfarin in plasma; in addition, it measures a probable metabolite of warfarin in urine. Further studies indicated that the metabolite may be hydroxy-warfarin.
The method was applied in determining the absorption and elimination of warfarin after oral and intravenous administration. Gastrointestinal absorption of the drug was rapid and complete. With both routes the plasma concentrations and prothrombinopenic response were similar, and the rate of disappearance from the plasma followed an exponential decay curve. A correlation was found between rate of elimination and biologic response — the slower the rate of elimination, the more pronounced the depression of prothrombin complex activity. The application of this dual approach, the simultaneous study of the metabolic fate of the drug and the prothrombinopenic response, should provide a more rational basis for the therapeutic use of anticoagulant drugs.
* This study was supported by U. S. Public Health Service Grant H-2754 and by a grant from the Warner-Chilcott Co. Throughout these studies, the sodium salt of warfarin was used.
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