title: Familial dysalbuminemic byperthyroxinemia may result in altered warfarin pharmacokinetics.
abstract: Two distinct genotypes that result in the amino acid substitutions R218P and R218H in subdomain 2A of human serum albumin (HSA) have been identified as the cause of familial dysalbuminemic hyperthyroxinemia (FDH). These substitutions increase the affinity of subdomain 2A for thyroxine by approximately 10-fold elevating plasma thyroxine levels in affected individuals. While many studies have examined the binding of thyroxine to FDH HSA, the binding of FDH HSA to drugs has not been widely investigated. The widely administered drug warfarin was selected as a model compound to study FDH HSA/drug interactions since it binds to subdomain 2A and its pharmacokinetics are dramatically influenced by HSA binding. Using two independent methods, fluorescence spectroscopy and equilibrium dialysis with radioactive warfarin, the binding of recombinant R218P, R218H, R218M and wild type HSA to warfarin was measured. Both methods showed an approximately 5-fold decrease in the affinity of R218P, R218H and R218M HSA for warfarin relative to wild type HSA. The Kd values determined by fluorescence spectroscopy for wild type, R218H, R218P and R218M HSA binding to warfarin were 1.35, 5.38, 5.61, and 8.34 microM, respectively. The values determined by equilibrium dialysis were 5.36, 29.5, 14.5, and 23.4 microM, 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.
authors.affiliation: Department of Biochemistry and Biophysics, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu 96822, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Petersen
authors.forename: C E
authors.initials: CE
authors.lastname: Ha
authors.forename: K
authors.initials: K
authors.lastname: Harohalli
authors.forename: D S
authors.initials: DS
authors.lastname: Park
authors.forename: N V
authors.initials: NV
authors.lastname: Bhagavan
mesh_terms: D019943:Amino Acid Substitution; D001120:Arginine / Q000235:genetics / Q000378:metabolism; D003956:Dialysis; D006639:Histidine / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006981:Hyperthyroxinemia / Q000097:blood* / Q000235:genetics*; D007700:Kinetics; D016254:Mutagenesis, Insertional; D009154:Mutation; D011485:Protein Binding; D012709:Serum Albumin / Q000235:genetics* / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D014859:Warfarin / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D012709:Serum Albumin; D006639:Histidine; D014859:Warfarin; D001120:Arginine