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, acenocoumaro l and phenprocoumon. Daily doses of up to 30 mg of the long-acting phe nprocoumon yielded a drug concentration of 85 mg/l (usual range 1-5 mg /l) but the international normalized ratio remained around 1, The plas ma half-life of phenprocoumon was approximately 350 h (normal 120-150 h). Thus, the resistance was not due to malabsorption or to an acceler ated metabolism of the drug. The level of vitamin K-1 (1,202 ng/l) was insufficient to induce resistance. Decarboxyprothrombin concentration s were low, demonstrating that the gamma-carboxylation of the precurso rs of the vitamin K-dependent coagulation factors was not effectively reduced. The concentration of vitamin K epoxide, normally increased un der oral anticoagulation, correlated to the vitamin K concentration (r (2) = 0.77) but the quotient epoxide/vitamin K remained 4-fold lower t han that of 22 warfarin-sensitive patients, suggesting an absence of b lockade of the vitamin K reductase by phenprocoumon, This resistance t o 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 .