A study of factors which determine the pharmacological response to vitamin K in coumarin anticoagulated rabbits.

The pharmacological response to vitamin K has been determined by measuring prothrombin complex activity (P.C.A.) in male New Zealand White rabbits anticoagulated (P.C.A. less than 20%) with the long acting 4-hydroxycoumarin brodifacoum, at a dose (10 mg/kg) which produces maximum antagonism of vitamin K1. Thus, according to current concepts, this animal model may be used to assess vitamin K requirements in the absence of a functional vitamin K-epoxide reductase. After intravenous administration of vitamin K1 (1 mg/kg) P.C.A. reached a maximum (64 +/- 19%) at 3 hr and then declined at a rate which corresponds to complete inhibition of clotting factor synthesis. Vitamin K2 (1 mg/kg) stimulated clotting factor synthesis for 2 hr, while cis-vitamin K1, vitamin K3, vitamin K1 2,3-epoxide and oral administration of vitamin K1 were ineffective. Plasma concentrations of vitamin K1 fell steeply during the 12 hr following administration of a pharmacological dose, and then declined with a terminal half-life of 18.9 +/- 9.0 hr. Comparison of the pharmacodynamic and pharmacokinetic data indicated that plasma concentrations in the range 0.4-1.0 microgram/ml are required for clotting factor synthesis in the limiting situation of maximum antagonism of vitamin K by coumarin anticoagulants. These findings explain why frequent and repeated administration of vitamin K1 may be necessary during coumarin poisoning.