Warfarin–Amiodarone Drug–Drug Interactions: Determination of [I]u/KI,u for Amiodarone and Its Plasma Metabolites

Abstract

A retrospective clinical evaluation in a cohort of 73 patients receiving stable anticoagulation therapy showed that the addition/elimination of amiodarone resulted in a 6–65% change in warfarin dose requirement. To evaluate the roles of amiodarone and its circulating metabolites in this highly variable inhibitory drug interaction, an LC-ESI+ MS/MS assay was developed for the quantitation of low concentrations of these compounds in human plasma, utilizing newly synthesized deuterated analogs as internal standards. KI’s were determined for the inhibition of (S)-warfarin 7-hydroxylation in human liver microsomes, by parent drug and metabolites, and unbound drug fractions (fu) were measured so that the ratio of unbound plasma concentration to the microsomal KI for unbound drug ([I]u/KI,u) could be calculated. From these ratios, we predict a minor metabolite, N,N-didesethylamiodarone, to be a major contributor to the drug interaction between warfarin and amiodarone.