The distribution and metabolism of D- and L-thyroxine (T4) were analyzed with specific reference to cellular and plasma protein determinants. Tracer quantities of 131I-L-T4 (Abbott Labs) and 125I-D-T4, synthesized by an iodine exchange reaction, were injected iv into intact male Sprague-Dawley rats. Both isomers were compared with respect to fractional plasma disappearance rates, total volumes of distribution, total metabolic clearance rates (MCRt), urinary and fecal excretory patterns, as well as distribution in liver, kidney and residual carcass. Appropriate corrections were made for trapped plasma within tissues by the use of tracer quantities of radioactive albumin. The relative strength of plasma binding of D- and L-T4 was determined both by equilibrium dialysis in diluted plasma, and by measurement of the fractional exit rates of labeled hormone from one compartment of undiluted plasma to another through a semipermeable membrane. Calculations based on these values and theoretical considerations developed in previous studies led to the following conclusions: 1) The increased MCRt of D-T4 compared to L-T4 is due both to diminished binding of D-T4 by plasma proteins and to an increase in the cellular metabolic clearance of D-T4. 2) Augmented cellular binding of D-T4 by liver and kidney results in diversion of the dextroisomer from other tissues. Despite previous estimates that the over-all hormonal potency of L-T4 exceeds that of D-T4 by a factor of 3 to 10, a 2 μg dose of D- and L-T4/100 g body weight in thyroidectomized rats raised the activity of the mitochondrial enzyme a-glycerophosphate dehydrogenase in both liver and kidney to approximately the same extent. Our findings support the possibility first proposed by Tapley et al. (Amer J Physiol 147: 1021, 1959) that differences in peripheral distribution between the D- and Lisomer may contribute to the observed differences in their over-all hormonal potency. Enhanced binding of D-T4 by liver and kidney appears to divert hormone from critical effector sites in other tissues.
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