Department of Medicinal Chemistry, University of Washington, Seattle, Washington, USA.
Clin Pharmacol Ther. 2012 Apr;91(4):709-17. doi: 10.1038/clpt.2011.283. Epub 2012 Mar 7.
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/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.
一项针对 73 例接受稳定抗凝治疗的患者的回顾性临床评估显示，胺碘酮的添加/消除导致华法林剂量需求发生 6%-65%的变化。为了评估胺碘酮及其循环代谢物在这种高度可变的抑制性药物相互作用中的作用，开发了一种液相色谱-电喷雾电离-串联质谱法，用于定量检测人血浆中这些化合物的低浓度，使用新合成的氘代类似物作为内标。测定了母体药物及其代谢物对人肝微粒体中（S）-华法林 7-羟化的抑制常数（K（I））值，并测量了未结合药物分数（f（u）），以便计算未结合血浆浓度与未结合药物的微粒体 K（I）的比值[I]（u）/ K（I，u）。根据这些比值，我们预测胺碘酮的一种次要代谢物，即 N，N-二去乙基胺碘酮（DDEA），是华法林和胺碘酮相互作用的主要贡献者。
