Key result
Amiodarone addition or elimination caused a 6-65% change in warfarin dose requirement, with the minor metabolite DDEA predicted as a major contributor to this inhibitory drug interaction.
Why the study?
Does amiodarone and its metabolites alter warfarin dose requirements in patients on stable anticoagulation?
Cohort (n=73)
Does amiodarone and its metabolites alter warfarin dose requirements in patients on stable anticoagulation?
The minor metabolite N,N-didesethylamiodarone (DDEA) is identified as a major contributor to the significant and highly variable drug-drug interaction between warfarin and amiodarone.
Variable warfarin dosing with amiodarone changes warrants INR vigilance; retrospective data leave open DDEA's role pending confirmation.
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.
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McDonald et al. (2012) conducted a cohort in Stable anticoagulation therapy (n=73). Amiodarone was evaluated on Change in warfarin dose requirement. Amiodarone addition or elimination caused a 6-65% change in warfarin dose requirement, with the minor metabolite DDEA predicted as a major contributor to this inhibitory drug interaction.