DIFFERENT TISSUE DISTRIBUTION, ELIMINATION, AND KINETICS OF THYROXINEAND ITS CONFORMATIONAL ANALOG, THE SYNTHETIC FLAVONOID EMD-49209 IN THE RAT

The synthetic flavonoids EMD 23188 and EMD 49209, developed as T-4 ana logs, displace T-4 from transthyretin, and in vitro they inhibit 5'-de iodinase activity. In vivo EMD 21388 causes tissue-specific changes in thyroid hormone metabolism. In tissues that are dependent on T-3 loca lly produced from T-4, total T-3 was diminished. It was not known whet her it was the presence of EMD interfering with 5'-deiodinase type II in tissues or the decreased T-4 (substrate) avail ability that caused the lowered T-3. To study whether the flavonoids enter tissues and, if this were the case, whether they enter tissues similarly, [I-125]EMD 49209 together with [I-131]T-4 were injected into female rats and rats pretreated with EMD 21388. Tissues were exracted and submitted to HPL C. [I-125]EMD 49209 disappeared quickly from plasma and enters periphe ral tissues; peak values were reached after 0.25-0.5 h. Then [I-125]EM D 49209 appeared in the intestines (after G h 40%; of the dose). Tissu e uptake of [I-131]T-4 was very rapid. EMD 21388 pretreatment caused a n increase in the excretion of [I-125]EMD 49209 into the intestines (4 0% after 0.25 h). The uptake of [I-131]T, increased, but not high enou gh to ensure normal tissue T-4 concentrations. In the 5'-deiodinase ty pe II-expressing tis sues, no [I-125]EMD 49209 could be detected. We c onclude that the decrease in T-3 locally produced from T-4 is caused b y the shortage of T-4 as substrate and not to a direct effect of EMD o n the activity of 5'-deiodinases I and II.