Effects of clofibrate and warfarin alone and in combination on the disposition of vitamin K1.

Clofibrate may interact with warfarin by potentiating its effects on vitamin K disposition. To examine this possibility, specifically labeled [3H]vitamin K was given intravenously to four healthy volunteers under conditions of no drug administration, administration of warfarin or clofibrate alone, or co-administration of both drugs. Clofibrate alone did not affect the disposition of tritiated vitamin K. Warfarin alone produced an accumulation in plasma of substantial amounts of vitamin K epoxide, a metabolite of vitamin K which is reconverted to vitamin K by a specific reductase. Although reconversion is apparently blocked to a large extent by warfarin, the plasma disappearance of tritiated vitamin K in the presence of warfarin is almost superimpossible to that observed in the absence of drugs. Clofibrate coadministration did not result in greater accumulation of vitamin K epoxide in plasma. These results indicate that clofibrate does not enhance the inhibition of the reductase enzyme. Analysis of the tritiated vitamin K plasma disappearance data indicates that the pool size of vitamin K in the body is small, and is turned over almost 10 times daily. The vitamin K epoxide data suggest that, in the absence of drugs, a relatively small proportion of the epoxide is reconverted to the vitamin.