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Different Tissue Distribution, Elimination, and Kinetics of Thyroxine and Its Conformational Analog, the Synthetic Flavonoid EMD 49209 in the Rat¹

Human and Animal Physiology, Agricultural University, Wageningen, The Netherlands; Henning Berlin (H.R.), Berlin; and Klinische Forschergruppe, Medizinische Poliklinik, Universität Würzburg (J.K.), Wurzburg, Germany; and Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas (G.M.d.E.), Madrid, Spain

Address all correspondence and requests for reprints to: Dr. Ir. J. P. Schröder-van der Elst, Department of Human and Animal Physiology, Agricultural University, Haarweg 10, 6709 PJ Wageningen, The Netherlands. E-mail: Janny.vanderElst{at}ALG.FMD.WAU.NL

The synthetic flavonoids EMD 23188 and EMD 49209, developed as T₄ analogs, displace T₄ from transthyretin, and in vitro they inhibit 5'-deiodinase activity. In vivo EMD 21388 causes tissue-specific changes in thyroid hormone metabolism. In tissues that are dependent on T₃ locally produced from T₄, total T₃ was diminished. It was not known whether it was the presence of EMD interfering with 5'-deiodinase type II in tissues or the decreased T₄ (substrate) availability that caused the lowered T₃. To study whether the flavonoids enter tissues and, if this were the case, whether they enter tissues similarly, [¹²⁵I]EMD 49209 together with [¹³¹I]T₄ were injected into female rats and rats pretreated with EMD 21388. Tissues were extracted and submitted to HPLC. [¹²⁵I]EMD 49209 disappeared quickly from plasma and enters peripheral tissues; peak values were reached after 0.25–0.5 h. Then [¹²⁵I]EMD 49209 appeared in the intestines (after 6 h 40% of the dose). Tissue uptake of [¹³¹I]T₄ was very rapid. EMD 21388 pretreatment caused an increase in the excretion of [¹²⁵I]EMD 49209 into the intestines (40% after 0.25 h). The uptake of [¹³¹I]T₄ increased, but not high enough to ensure normal tissue T₄ concentrations. In the 5'-deiodinase type II-expressing tissues, no [¹²⁵I]EMD 49209 could be detected. We conclude that the decrease in T₃ locally produced from T₄ is caused by the shortage of T₄ as substrate and not to a direct effect of EMD on the activity of 5'-deiodinases I and II.

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