Effect of warfarin on plasma and liver vitamin K levels and vitamin K epoxide reductase activity in relation to plasma clotting factor levels in rats

Abstract

Changes in plasma and liver vitamin K 1 and vitamin K 1 epoxide levels, liver microsomal vitamin K epoxide reductase activity, and plasma clotting factor II and VII levels were determined in rats after a single injection of warfarin (2.5 mg/kg, s.c.). The plasma and liver vitamin K 1 levels gradually decreased after warfarin injection, attaining the lowest values at 2–3 hrs and remaining low for 48 hrs. They then returned to the control levels at 72 hrs. The changes in vitamin K 1 epoxide levels were opposite, with an increase being seen soon after the warfarin injection, the highest values at 3 hrs and a gradual decrease to the initial levels occurring subsequently. The combined levels of vitamin K 1 plus vitamin K 1 epoxide, however, remained almost constant in both plasma and liver after the warfarin injection. The liver vitamin K epoxide reductase activity decreased to its lowest level soon after the injection and then gradually increased after 12 hrs, but the activity at 72 hrs was only about 30% of the initial activity. The plasma clotting factor levels gradually decreased after the injection, bottomed at 24 hrs and then began to increase, recovering almost to the initial levels at 72 hrs. A positive correlation was found between plasma and liver levels for both vitamin K 1 and vitamin K 1 epoxide, and the slope of the vitamin K 1 epoxide curve was steeper than that for vitamin K 1 in the warfarin-treated rats. A similar positive correlation was found for both vitamin K 1 and vitamin K 1 epoxide after vitamin K 1 injection in normal untreated rats, but the slope of the vitamin K 1 epoxide curve was much shallower. These results suggest that warfarnn inhibits vitamin K eposide reductase and decreases blood clotting factor synthesis, thus increasing plasma and liver vitamin K 1 epoxide levels. A vitamin K epoxide reductase activity one third of that in normal rats is sufficient to maintain normal reduction of vitamin K 1 epoxide and synthesis of blood clotting factors.