Optimized kinetics of reverse-triiodothyronine distribution and metabolism in the rat: dominance of large, slowly exchanging tissue pools for iodothyronines.

We have estimated numerous physiological parameters of production, interpool transport, distribution, and metabolism of rT3 in the major rT3 pools of the unanesthetized male Sprague-Dawley rat. These results also have been combined with similar results for T3 and T4, generating a composite model for all three iodothyronines. Three different approaches were used to analyze the rT3 data, determined from five optimally timed blood samples collected in new tracer kinetic studies and processed by Sephadex chromatography and RIA. A model-structure independent approach generated a plasma clearance rate of 2.82 (ml/min)/100 g BW, a plasma turnover rate of 1.05 min-1, a plasma-to-total tissue flux of 0.107 (ng/min)/100 g BW and a plasma appearance rate (PAR) of 0.061 (ng/min)/100 g BW, the latter being the product of the plasma clearance rate and the endogenous rT3 plasma concentration. Multicompartmental analysis resulted in additional parameters of physiological interest, many only as ranges or minimum and maximum possible values, owing to complex factors intrinsic in rT3 kinetics. Whole body rT3 production can be as low as 0.061 (=PAR), and as high as 0.377 (ng/min)/100 g BW, i.e. possibly as much as 5 times greater than the PAR, the conventional estimate of production rate. Plasma contains only 3-12% of total body rT3 (Qtot); slow tissue pools, that exchange rT3 slowly with plasma, possibly muscle, skin, and brain, contain 63-95% of Qtot, and produce more than 42% of total body rT3 from T4 locally; and fast tissues like liver and kidney contain 2-26% of Qtot, and produce more than 12% of total body rT3 from T4 locally. The plasma equivalent distribution volume (VD) of rT3 is 38-146 ml/100 g BW, and its whole body mean residence time is only 14-52 min, both of which are an order of magnitude smaller than corresponding T3 values; but VD for rT3 and T4 are roughly the same. Noncompartmental analysis underestimated VD and mean residence time by somewhere between a factor of 1.2 and 4.6. Overall, these results indicate that tissue pools that exchange rT3 slowly with the plasma pool contain the majority of rT3, T3, and T4 in steady state; and these tissues also are implicated as major sites of T4 monodeiodination, to both rT3 and T3.