The effect of alterations in metabolic status on the peripheral metabolism of thyroxine (T₄) has been studied in thyroidectomized rats by an isotopic equilibration technique. In hypothyroid animals total T₄ clearance rate was decreased as a result of decrease in the activity of both fecal and deiodinative routes of T₄ metabolism. T₄ distribution space was unchanged or very slightly decreased, and the net thyroid hormone binding affinity of the serum proteins, as judged by in vitro uptake tests, was increased little, if at all.

In animals made thyrotoxic by daily administration of 10 M—g T₄/ISO g bw daily, total T₄ clearance rate was more than doubled, this as a consequence of increases in both fecal and deiodinative clearance. Total T₄ distribution space was slightly increased and net thyroid hormone binding affinity of serum slightly decreased. Qualitatively similar results were obtained when animals were made thyrotoxic by administration of 3.3 µg L—triiodothyronine/150 g bw daily.

Since the changes in hormonal metabolism that accompanied hypothyroidism or thyrotoxicosis were often associated with changes in extracellular hormonal binding, they cannot be ascribed with certainty to alterations in cellular factors that influence hormonal metabolism. Nevertheless, changes in extracellular binding were not invariably present and, when present, were often small. Moreover, changes in T₄ distribution space, which should reflect alterations in extracellular binding, were also inconstant and were relatively much smaller than the changes seen in fecal and deiodinative clearance rates. For these reasons, it is suggested that the slowing and acceleration of T₄ metabolism which occurred in the hypothyroid and thyrotoxic rats, respectively, are the result primarily of changes in the binding affinity or degradative activity of the tissues per se. (Endocrinology92: 1028, 1973)