Familial dysalbuminemic hyperthyroxinemia may result in altered warfarin pharmacokinetics

Two distinct genotypes that result in the amino acid substitutions R218P an d R218H in subdomain 2A of human serum albumin (HSA) have been identified a s the cause of familial dysalbuminemic hyperthyroxinemia (FDH). These subst itutions increase the affinity of subdomain 2A for thyroxine by approximate ly 10-fold elevating plasma thyroxine levels in affected individuals. While many studies have examined the binding of thyroxine to FDH HSA, the bindin g of FDH HSA to drugs has not been widely investigated. The widely administ ered drug warfarin was selected as a model compound to study FDH HSA/drug i nteractions since it binds to subdomain 2A and its pharmacokinetics are dra matically influenced by HSA binding. Using two independent methods, fluores cence spectroscopy and equilibrium dialysis with radioactive warfarin, the binding of recombinant R218P, R218H, R218M and wild type HSA to warfarin wa s measured. Both methods showed an approximately 5-fold decrease in the aff inity of R218P, R218H and R218M HSA for warfarin relative to wild type HSA. The K-d values determined by fluorescence spectroscopy for wild type, R218 H, R218P and R218M HSA binding to warfarin were 1.35, 5.38, 5.61, and 8.34 mu M, respectively. The values determined by equilibrium dialysis were 5.36 , 29.5, 14.5, and 23.3 mu M, respectively. Based on the above findings one would expect the free serum warfarin concentration in homozygous R218P and R218H FDH patients to be elevated about 5-fold, resulting in about a 5-fold reduction in the serum half-life of the drug. (C) 2000 Elsevier Science Ir eland Ltd. All rights reserved.