Vitamin K metabolism in a patient resistant to vitamin K antagonists.
We investigated various pharmacokinetic and pharmacodynamic parameters in a 63-year-old man, resistant to warfarin, fluindione, acenocoumarol and phenprocoumon. Daily doses of up to 30 mg of the long-acting phenprocoumon yielded a drug concentration of 85 mg/l (usual range 1-5 mg/l) but the international normalized ratio remained around 1. The plasma half-life of phenprocoumon was approximately 350 h (normal 120-150 h). Thus, the resistance was not due to malabsorption or to an accelerated metabolism of the drug. The level of vitamin K1 (1,202 ng/l) was insufficient to induce resistance. Decarboxyprothrombin concentrations were low, demonstrating that the gamma-carboxylation of the precursors of the vitamin K-dependent coagulation factors was not effectively reduced. The concentration of vitamin K epoxide, normally increased under oral anticoagulation, correlated to the vitamin K concentration (r2 = 0.77) but the quotient epoxide/vitamin K remained 4-fold lower than that of 22 warfarin-sensitive patients, suggesting an absence of blockade of the vitamin K reductase by phenprocoumon. This resistance to all the molecular forms of the vitamin K antagonists is most likely due to a reduced affinity of the drugs to a mutant vitamin K reductase.
Keréveur
A
A
Service d'Hématologie biologique, Hôtel-Dieu, Paris, France.
Leclercq
M
M
Trossaërt
M
M
Dupeyron
J P
JP
Parent
F
F
Horellou
M H
MH
Conard
J
J
Bachmann
F
F
Samama
M M
MM
D004351:Drug Resistance; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors; D010644:Phenprocoumon / Q000097:blood; D014812:Vitamin K / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism*; D010837:Vitamin K 1 / Q000097:blood; D014859:Warfarin / Q000097:blood
D014812:Vitamin K; D014859:Warfarin; D010837:Vitamin K 1; D016660:NAD(P)H Dehydrogenase (Quinone); D010644:Phenprocoumon