%0 Journal Article %A PETER REN %A RONALD E. LALIBERTE %A ROBERT G. BELL %T Effects of Warfarin, Phenylindanedione, Tetrachloropyridinol, and Chloro-vitamin K1 on Prothrombin Synthesis and Vitamin K Metabolism in Normal and Warfarin-Resistant Rats %D 1974 %J Molecular Pharmacology %P 373-380 %V 10 %N 3 %X Anatagonists of vitamin K—warfarin, phenylindanedione the 2-chloro analogue of vitamin K1, and tetrachloropyridinol—blocked prothrombin synthesis completely and without a lag period in the rat. Experiments to determine the mode of action of the antagonists indicated that they could be divided into two groups. The inhibition of prothrombin synthesis by all four antagonists was reversed by vitamin K1, but the inhibition in Sprague-Dawley rats by group I (warfarin and phenylindanedione) was not reversed by phylloquinone epoxide, beause the group I compounds inhibited the conversion of [3H] phylloquinone epoxide to the active vitamin, [3H]vitamin K1, and caused the accumulation of [3H] phylloquinone epoxide in rats that had received injections of the tritiated vitamin. It is proposed that group I compounds were ineffective in blocking prothrombin synthesis in warfarin-resistant rats because in these animals the conversion from epoxide to K1 is not as sensitive as in normal animals. Consequently the epoxide can stimulate prothrombin synthesis in the presence of group I compounds in the resistant strain. In contrast, the inhibition of prothrombin synthesis by group II (tetrachloropyridinol and 2-chloro-vitamin K1) was reversed by epoxide, because these compounds inhibited the [3H] phylloquinone epoxide to [3H] vitamin K1 conversion much less than those of group I. Similarly, the effect of group II on the metabolism of [3H] vitamin K1 was much smaller than that of group I. Group II compounds blocked prothrombin synthesis in warfarin-resistant animals at least as well as in Sprague-Dawley rats. These results are consistent with the idea that coumarin and indanedione anticoagulants (group I) inhibit prothrombin synthesis by causing the accumulation of an inhibitor of the vitamin, phylloquinone epoxide, and that 2-chloro-vitamin K1 and tetrachloropyridinol (group II) act at another site. ACKNOWLEDGMENTS The authors wish to acknowledge the invaluable technical assistance of Ms. Deborah Chisholm, Ms. Laurel Truesdell, and Mr. Paul Caldwell. %U https://molpharm.aspetjournals.org/content/molpharm/10/3/373.full.pdf