USE OF A COMPETITIVE VITAMIN K ANTAGONIST, 2-CHLORO-3-PHYTYL-1,4-NAPHTHOQUINONE, FOR THE STUDY OF THE MECHANISM OF ACTION OF VITAMIN K AND COUMARIN ANTICOAGULANTS

¹ Department of Biochemistry, Queen's University, Kingston, Ontario, Canada

When the optimal dose of vitamin K₁ in vitamin K-deficient (0.5 µg/100 g) or coumarin anticoagulant-pretreated (100 µg/100 g) rats is given i.v. together with the 2-chloro analog of vitamin K₁ (2-chloro-3-phytyl-1,4-naphthoquinone) the increase of the plasma level of clotting factor VII is partially or completely inhibited. Although there is a 200-fold difference between the optimal doses of vitamin K₁, the doses of the chloro analog required for partial or complete inhibition in vitamin K-deficient or coumarin anticoagulant-pretreated rats are nearly the same (15-25 and 80-100 µg/100 g, respectively). When the doses are increased, but the ratio of vitamin K₁ and the chloro analog is kept constant, the inhibition remains constant for the ratio of 2:1 in coumarin anticoagulant-pretreated but increases for the ratio of 1:20 and 1:30 in vitamin K-deficient animals. However, when in vitamin K-deficient animals increasing doses of a ratio of vitamin K₁ and the chloro analog of 2:1 are tested, the inhibition is found to remain constant. These findings can be explained by the hypothesis that the mechanism of action of vitamin K₁ involves a reversible combination with a receptor, which is preceded by an interaction which is of limited capacity and is susceptible to irreversible inhibition by coumarin anticoagulants. This interaction may possibly, but not necessarily, involve a specific transport mechanism. However, when larger doses are administered, vitamin K1 can reach the receptor site by an alternate route, posibly, but not necessarily, simple diffusion, which is not inhibited by coumarin anticoagulants. The chloro analog acts as a competitive antagonist at the receptor site but, in contrast to vitamin K₁, lacks affinity for the specific transport-like step and can reach the receptor site only by the alternate route. An analysis of these interrelations predicts that in animals anticoagulated by pretreatment with the chloro analog of vitamin, simultaneous administration of warfarin should inhibit the response to vitamin K₁, but that the inhibition should disappear with increasing doses of a constant dose ratio of vitamin K and warfarin, if the warfarin has no effect on the alternate route. This prediction has been confirmed experimentally and gives additional support to the proposed hypothesis.

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				J. Lowenthal and H. Birnbaum Vitamin K and Coumarin Anticoagulants: Dependence of Anticoagulant Effect on Inhibition of Vitamin K Transport Science, April 11, 1969; 164(3876): 181 - 183. [Abstract] [PDF]