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Endocrinology Vol. 144, No. 2 552-558
Copyright © 2003 by The Endocrine Society

ARTICLE

Dronerarone Acts as a Selective Inhibitor of 3,5,3'-Triiodothyronine Binding to Thyroid Hormone Receptor-{alpha}1: In Vitro and in Vivo Evidence

H. C. van Beeren, W. M. C. Jong, E. Kaptein, T. J. Visser, O. Bakker and W. M. Wiersinga

Departments of Endocrinology and Metabolism, and Cardiology (W.M.C.J.), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; and Department of Internal Medicine, Erasmus University Medical Center (E.K., T.J.V.), 3015 GE Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Dr. H. C. van Beeren, Department of Endocrinology and Metabolism, Academic Medical Center F5-171, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail: h.c.vanbeeren{at}amc.uva.nl.

Dronedarone (Dron), without iodine, was developed as an alternative to the iodine-containing antiarrhythmic drug amiodarone (AM). AM acts, via its major metabolite desethylamiodarone, in vitro and in vivo as a thyroid hormone receptor {alpha}1 (TR{alpha}1) and TRß1 antagonist. Here we investigate whether Dron and/or its metabolite debutyldronedarone inhibit T3 binding to TR{alpha}1 and TRß1 in vitro and whether dronedarone behaves similarly to amiodarone in vivo.

In vitro, Dron had a inhibitory effect of 14% on the binding of T3 to TR{alpha}1, but not on TRß1. Desethylamiodarone inhibited T3 binding to TR{alpha}1 and TRß1 equally. Debutyldronedarone inhibited T3 binding to TR{alpha}1 by 77%, but to TRß1 by only 25%.

In vivo, AM increased plasma TSH and rT3, and decreased T3. Dron decreased T4 and T3, rT3 did not change, and TSH fell slightly. Plasma total cholesterol was increased by AM, but remained unchanged in Dron-treated animals. TRß1-dependent liver low density lipoprotein receptor protein and type 1 deiodinase activities decreased in AM-treated, but not in Dron-treated, animals. TR{alpha}1-mediated lengthening of the QTc interval was present in both AM- and Dron-treated animals.

The in vitro and in vivo findings suggest that dronedarone via its metabolite debutyldronedarone acts as a TR{alpha}1-selective inhibitor.




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