An experimental model in dogs for studying interactions of drugs with bishydroxycoumarin

Experiments were carried out in dogs to investigate potentially dangerous interactions of drugs with bishydroxycoumarin that can occur in man. Dogs were treated orally with 1 mg. per kilogram of body weight of bishydroxycoumarin every other day for 39 to 44 days, and constant elevated prothrombin times and plasma levels of drug were obtained. When the dogs were given 10 mg. per kilogram of phenobarbital daily, the prothrombin time fell to normal and anticoagulant was no longer detectable in the plasma. If the dose of bishydroxycoumarin was then increased sevenfold, prothrombin times and plasma levels of drug were only slightly elevated. Phenobarbital administration was stopped, but bishydroxycoumarin was continued. Ten to 15 days after discontinuing phenobarbital, plasma levels of bishydroxycoumarin increased markedly, and all dogs developed severe hemorrhages. Administration of barbital also decreased the plasma level of bishydroxycoumarin and antagonized the activity of the anticoagulant, but barbital was less potent than phenobarbital. These effects can be explained by a stimulatory effect of the barbiturates on the metabolism of bishydroxycoumarin. When phenylbutazone and tolbutamide were given under the same conditions as the barbiturates, anticoagulant activity was first potentiated and then antagonized. This can be explained by initial displacement of bishydroxycoumarin from binding sites on plasma protein followed by a stimulatory effect of phenylbutazone and tolbutamide on the metabolism of bishydroxycoumarin.