Changes in the pharmacology of warfarin during long-term administration in dogs

Patients receiving an apparently appropriate maintenance dosage of oral anticoagulant may show unexpected changes in clotting status without readily identifiable cause. The object of this study was to determine whether a consistent change in the pharmacology of warfarin could account for the clinical observations during long-term dosing. Eleven healthy adult dogs received constant daily oral doses of warfarin for 4 weeks. Plasma warfarin concentration (W), measured by gas chromatography, and prothrombin time (PT), measured by the one-stage assay of Quick, were determined daily. W and PT decreased significantly (p less than 0.05) during the last 2 weeks of long-term treatment. No pharmacodynamic changes were observed after prolonged warfarin treatment, suggesting that the decreases in PT were due solely to the decreased W. The decrease in W was not due to an increased free warfarin fraction or to a reduction in W absorption from the gut. The reproducibility of these results was demonstrated in a second group of experiments done 1 month after the first set of studies. Over the entire group of dogs there was no consistent change in warfarin clearance during prolonged dosing. We conclude that during constant daily dosing, W and PT reach early peak values, after which they decrease to levels significantly below peak levels. These results suggest that clinical anticoagulation may require multiple dosage adjustments despite the early attainment of apparently therapeutic anticoagulant regulation with a fixed dosage schedule.