Analysis of Pharmacokinetic Interaction Between Amiodarone/Desethylamiodarone and Metoprolol

E Hrudikova-Vyskocilova,I Kacirova,J Duricova,R Urinovska,M Grundmann

doi:10.1016/j.clinthera.2017.05.261

E Hrudikova-Vyskocilova, I Kacirova + Show 3 more

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https://doi.org/10.1016/j.clinthera.2017.05.261

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Abstract

Amiodarone (AM) is the most effective antiarrhythmic drug and its major metabolite desethylamiodarone (DEA) is pharmacologically effective as well. A β1 blocker metoprolol (M) is metabolized to alpha-hydroxymetoprolol (OH-M) by CYP2D6 and both AM and DEA inhibit this enzyme. We analysed interaction between amiodarone/ desethylamiodarone and metoprolol. We analyzed retrospectively 69 serum concentrations of AM, DEA, M and OH-M measured by HPLC method with UV or fluorescent detection from 29 patients (years 2014-2015). We estimated the concentration/dose ratio of metoprolol, metabolic ratio of M/OH-M and OH-M/M, and metoprolol clearance (Cl) and elimination half-time (t1/2) depending on concentrations of AM, DEA and sum AM+DEA. Phenotypization of patients was performed by metabolic ratio (MR) of M/OH-M concentrations. Statistically significant correlation was observed between concentration/dose ratio of metoprolol and concentrations of both AM and DEA as well as between metabolic ratio M/OH-M and concentrations of both sum AM+DEA and DEA itself. No statistically significant correlation was found between t1/2 a Cl of metoprolol and concentrations of AM or DEA. Phenotypization of CYP2D6 divided individual samples into groups with MR<1.0 (n=17) and MR 1.0-10.5 (n=7) for serum taking after metoprolol administration and with MR<1.0 (n=31) and MR 1.0-10.5 (n=7) for serum taking before metoprolol administration. We showed that an increasing concentrations of amiodarone and desethylamiodarone led to lower dose of metoprolol to achieved the same serum concentration. Increase of DEA and sum of AM+DEA concentrations led to decrease of metoprolol metabolization by inhibition of CYP2D6. The results indicate that important drug-drug interaction between metoprolol and amiodaron is due to inhibition of CYP2D6, mainly by DEA. Therefore wen the combination of drugs is administered careful therapeutic monitoring of not only metoprolol but also of amiodarone including DEA is recommended.

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