Genetic control of interindividual variations in racemic warfarin binding to plasma and albumin of twins

E-ISSN： 1532-6535|22|6|831-842

ISSN： 0009-9236

Source： CLINICAL PHARMACOLOGY & THERAPEUTICS, Vol.22, Iss.6, 1977-12, pp. : 831-842

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Abstract

Warfarin binding to plasma as well as to charcoal‐treated purified albumin was studied in monozygotic (MZ) and dizygotic (DZ) twins by equilibrium dialysis. The association constants of warfarin binding and the number of warfarin binding sites per molecule were more similar within MZ than within DZ twins. These data indicate that genetic factors control interindividual variations in warfarin‐albumin association constants and in the number of warfarin binding sites per albumin molecule. A heritability index of a .87 was obtained for the association constant of warfarin binding to plasma and of 0.89 for warfarin binding to albumin. Heritability indices of 0.80 and 0.85 were obtained for the number of warfarin sites per albumin molecule in plasma and albumin, respectively. When the values of Ka and n for warfarin binding to albumin are plotted for the 44 individuals in this study, the distribution of Ka as well as n appears to be trimodal. The distribution of n falls into three classes, with 19 having an average binding site of 0.9, 14 having an average binding site of 1.4, and 3 having an average binding site of 2.1. Since this distribution conforms to a Hardy‐Weinberg equilibrium with gene frequencies of 0.72 and 0.28 and since the average number of binding sites is close to integral numbers of 1 and 2, it is tempting to speculate that these data disclose for the first time a common polymorphism of the albumin molecule affecting both nand Ka such that the phenotypic variations are controlled by two alleles at a single genetic locus. Since the number of subjects is too small for this distribution analysis to be completely secure, family studies will be required to determine whether such a polymorphism exists. Ka and n, though significantly correlated, have r values that are not very high (for isolated albumin, r = 0.63 for Ka vs n in MZ twins, p < O.Ol;r = 0.34 for Ka vs n in DZ twins, p = 0.05; for whole plasma, r = 0.78 for n vs Ka in MZ twins, p < 0.01; r = 0.57 for n vs Ka in DZ twins, p < 0.0 1). With respect to avidity of warfarin binding and number of warfarin sites per albumin molecule, these results suggest that inherited structural differences in the albumin molecule may affect the transport of certain drugs within the body of