Comparison of the metabolism and distribution of L-triiodothyronine and triiodothyroacetic acid in the rat: a possible explanation of differential hormonal potency.

Previous studies from this laboratory have shown that nuclear displacement of triiodothyronine (T3) is more rapidly dissipated after iv injection of triiodothyroacetic acid (triac) than after equimolar doses of T3. This suggested that the discrepancy between the strong nuclear binding of triac and its relatively weak thyromimetic effect could be explained by a more rapid fractional rate of triac metabolism. To test this hypothesis, tracer studies with radioactively labeled T3 and triac were carried out in normal male Sprague-Dawley rats. Noncompartmental analysis showed that the average residence time of tracer triac in the exchangeable compartment was 5.5 h compared with 10.9 h for T3. The metabolic clearance rate of triac was 14.4 ml/h/100 g BW and of T3 17.6 ml/h/100 g. The average distribution space of triac was 78.2 ml/100 g and of T3 190.7 ml/100 g. The fraction of isotope excreted via the fecal route was 0.46 for triac and 0.41 for T3. Triac was approximately 16 times as firmly bound to plasma proteins as was T3. Isotopic studies suggested that a rapid exchange of tracer triac occurred between plasma, cytosol, and nuclei, similar to previously observed relationships for T3. Based on the daily dose of T3 and triac required to maintain a normal concentration of alpha-glycero-phosphate dehydrogenase in thyroidectomized animals, the T3:triac potency ratio was estimated to be 3.0. Our observations support the concept that a shorter duration of nuclear occupancy observed in previous experiments can be attributed to a more rapid fractional metabolism of triac and may explain the lesser hormonal effect of this compound. Since labeled triac could not be identified in nuclear extracts after the injection of isotopically labeled T3, it appears unlikely that the initiation of hormonal effects by T3 at the nuclear level is dependent on its prior conversion to triac.