Abstract
To clarify the mechanism (s) contributing to the large interpatient variability in the dose of warfarin required for producing similar anticoagulant effects among cardiac patients, we performed; a) a retrospective medical chart survey to search for clinical variables associated with an interpatient variability of warfarin doses in 107 patients exhibiting stable anticoagulant effect during oral warfarin therapy administered constant doses of 0.5 to 7 mg; and b) a prospective clinical study in which steady-state total and unbound serum concentrations of warfarin enantiomers, determined with a newly developed chiral HPLC-UV detection method combined with an ultrafiltration technique, were correlated with the international normalized ratios (INRs) of prothrombin time in 8 patients given a chronic oral warfarin therapy. Results obtained from the medical chart survey showed that there was a 14-fold difference in the maintenance doses of warfarin among the patients and that the dose exhibited a significant age-dependent reduction (r=-0.26, p<0.01) Rirthermore, The clinical study revealed that while a significant correlation was observed neither between the warfarin doses and INR nor between the total serum concentrations of warfarin enantiomers and INR, there were significant (r>0.74, p<0.05) correlations between the unbound concentrations of both warfarin enantiomers and INR. These data suggest that the pharmacokinetic-dynamic relationship of warfarin should be analyzed based upon serum unbound enantiomer concentrations. It remains unclear whether S-warfarin possessing an anticoagulant effect 3 to 5 times more potent than its optical congener would have a greater contribution to the interpatient variability in the anticoagulant effects than that of R-warfarin.
