Warfarin-amiodarone drug-drug interactions: Determination of [I] u/K I,u for amiodarone and its plasma metabolites

摘要

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, a liquid chromatography-electrospray ionization-tandem mass spectrometry assay was developed for the quantitation of low concentrations of these compounds in human plasma, using newly synthesized deuterated analogs as internal standards. Inhibition constant (K I) values were determined for the inhibition of (S)-warfarin 7-hydroxylation in human liver microsomes by the parent drug and its metabolites, and the unbound drug fractions (f u) were measured in order to calculate the ratio of unbound plasma concentration to the microsomal K I for the unbound drug (I u/K I,u). From these ratios, we predict that a minor metabolite of amiodarone, namely, N,N-didesethylamiodarone (DDEA), is a major contributor to the interaction between warfarin and amiodarone.