Vitamin K deficiency amplifies anticoagulation response to ximelagatran: possible implications for direct thrombin inhibitors and their clinical safety.
Dietary vitamin K is known to influence the anticoagulation response to warfarin. It is possible that dietary vitamin K availability also influences the pharmacological activity of other oral anticoagulants, which target the vitamin-K dependent clotting proteins in the coagulation cascade. This study examined whether vitamin K insufficiency affected anticoagulation response to the direct thrombin inhibitor, ximelagatran. Anticoagulation response to ximelagatran and warfarin in rats on a normal diet was compared to those on a vitamin K deficient diet. Ximelagatran and warfarin increased prothrombin time (PT) by 1.4- and 1.3-fold, activated partial thromboplastin time (APTT) by 1.8- and 1.4-fold and ecarin clotting time (ECT) by 6.8- and 1.2-fold, respectively, in rats on normal diet. Vitamin K deficient diet alone caused modest increases in PT, APTT and ECT. The anticoagulant activity of both ximelagatran and warfarin was significantly greater in rats on vitamin K deficient diet (6.1- and 12.3-fold for PT, 2.6- and 5.1-fold for APTT and 2.9- and 1.6-fold for ECT, respectively) compared to those on normal diet. Factor II activity was reduced by both ximelagatran (58%) and warfarin (44%) in rats on normal diet. However, factor II activity was virtually abolished (<0.1%) by both drugs in rats on vitamin K deficient diet. The results suggest that oral anticoagulant drugs, whose primary site of action is not within the vitamin K cycle, may also exhibit variability in clinical response due to dietary variation as the established coumarin drugs such as warfarin.
Kamali
Farhad
F
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. farhad.kamali@ncl.ac.uk
Wood
Peter
P
Ward
Alan
A
D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects* / Q000627:therapeutic use*; D001384:Azetidines / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001596:Benzylamines / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014812:Vitamin K / Q000097:blood; D014813:Vitamin K Deficiency / Q000188:drug therapy*
D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; D014812:Vitamin K; C426686:ximelagatran; D013917:Thrombin