Effect of 5-fluorouracil on the anticoagulant activity and the pharmacokinetics of warfarin enantiomers in rats.

The interaction between the antineoplastic agent 5-fluorouracil (5-FU) and the oral anticoagulant warfarin enantiomers was investigated in rats. An increase in hypoprothrombinaemic response, assessed by means of percent changes of prothrombin complex activity and clotting factor VII activity, to warfarin, was observed following oral administration of 1.5 mg/kg racemic warfarin to rats during a 8-day intraperitoneal dose regimen of 5-FU (13.3 mg/kg daily). 5-FU had no apparent effect on the baseline blood coagulation, the in vitro rat serum protein binding as well as the absorption and distribution of the S- and R-enantiomers of warfarin in rats. Yet treatment with 5-FU produced a significant decrease in the total serum clearance value of S-warfarin in rats. The decreased total clearance was attributed mainly to a significant decrease in the formation rate of the overall oxidative metabolites of the more potent S-enantiomer of warfarin.