Comprehensive kinetics of thyroxine distribution and metabolism in blood and tissue pools of the rat from only six blood samples: dominance of large, slowly exchanging tissue pools.

Abstract

We have estimated 24 physiological parameters of production, interpool transport, distribution, and metabolism of T4 in the major T4 pools of the unanesthetized male Sprague-Dawley rat from six optimally timed blood samples (at 1, 5, 23, 115, 465, 1440 min) and a comprehensive model and analysis. Despite 10-fold lower concentrations of T4 reported in tissues that exchange T4 with plasma at a slow rate (e.g. skeletal muscle) compared with rapidly exchanging tissues like liver and kidney, the composite of slow tissue pools contains 57% of total body T4, with only 17% in fast pools and 26% in plasma. At least 14% of the 0.53 ng/min/100 g BW of T4 secreted is converted to T3 in slow tissue pools, and 24% is an upper bound on whole body T4 to T3 conversion. The T4 fractional turnover rates in fast and slow tissue pools (0.154 and 0.007 min-1), corresponding tissue to plasma T4 fractional transport rates (0.152 and 0.006 min-1), and relative fluxes of T4 from plasma to fast vs. slow tissues (88% vs. 12%) were all found to be approximately the same as those we have reported for T3. As a consequence, the ratio of the fractional (or clearance) rate of entry of T3 into tissue to that of T4 was found to be equal to the ratio of the plasma equivalent distribution volume of T3 to that of T4 in the tissue, which also is the ratio of relative pool sizes of T3 and T4 in the tissue to those in plasma. This ratio (approximately 11) is approximately the same for all tissues, slow and fast, and it is also the same as the ratio of the net binding of T3 and T4 to plasma proteins. Finally, despite a 10 times slower early disappearance rate for a bolus of T4 than for T3 and reported single half-lives for T4 3-6 times greater, T4 actually spends only a third longer time (17.5 h) in the whole system, mostly in slow pools, before ultimate irreversible disposal.