The effect of phenobarbitone pre-treatment on vitamin K1 disposition in the rat and rabbit

The effect of phenobarbitone enzyme induction on the pharmacokinetics of an intravenous pharmacological dose (1 mg/kg) of vitamin K1 was studied in the rabbit. Phenobarbitone pretreatment significantly (P less than 0.01) increased the plasma clearance of vitamin K1 and decreased the terminal (beta) half-life from 2.08 +/- 0.56 to 0.99 +/- 0.30 hr. However, phenobarbitone pretreatment did not alter the pharmacodynamic response to vitamin K1 measured as the increase in prothrombin complex activity, in brodifacoum-anticoagulated rabbits. In the rat, phenobarbitone enzyme induction increased the extent and rate of biliary excretion of polar vitamin K1 metabolites following intravenous administration of the vitamin. Perturbation of vitamin K1 metabolism by phenobarbitone enzyme induction is not dependent on the concentration of the vitamin. The greater hepatic elimination resulted in lower systemic blood concentrations of both vitamin K1 and the 2,3-epoxide. A similar reduction in the concentration of vitamin K1 in the blood of epileptic mothers treated with anticonvulsants such as phenobarbitone may explain the coagulation defect frequently observed in their offspring [K. R. Mountain, J. Hirsh and A.S. Gallus, Lancet ii, 265 (1970)].