Abstract
The purpose of this investigations was to determine the mechanism of the potentiating effect of phenylbutazone on the anticoagulant action of dicumarol, with particular emphasis on the relationsip between anticoagulant effect and drug concentration in the liver. Single doses of dicumarol, 2 to 8 mg/kg, were administered intraperitoneally or intravenously to adult male Sprague-Dawley rats. Steady-state levels of phenylbutazone in the plasma (84.5 mg/l, S.D. 35.0 mg/l; n = 73) were maintained by repeated administration of that drug. Prothrombin complex activity and concentrations of dicumarol in the plasma and liver were determined as a function of time. Phenylbutazone had no apparent anticoagulant action of its own but exerted a pronounced potentiating effect on the anticoagulant action of dicumarol. The half-life, the apparent volume of distribution and the plasma/liver concentration ratio of dicumarol were not significantly affected by phenylbutazone. On the other hand, phenylbutazone had a pronounced influence not only on the relationship between the anticoagulant effect and the concentration of dicumarol in the plasma, but also on the effect-concenstration relationship in the liver. The potentiating action of phenylbutazone on the anticoagulant effect of dicumarol is therefore not due to a shift of dicumarol from plasma to liver.
Footnotes
- Received March 26, 1973.
- Accepted May 29, 1973.
- © 1973 by The Williams & Wilkins Company
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