Effect of 5,5'-Diphenylhydantoin on the Metabolism of L-Thyroxine-131I in the Rat

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Abstract
Because 5,5[image]-diphenylhydantoin (DPH) decreases tht concentration of serum protein-bound iodine (PB1) in man, the effect of this drug on the metabolism of L-thyroxine in the rat and in the isolated rat liver was studied. DPH produced a decrease in concentration of PBI in the rat although it did not alter the uptake of T3-I131 [3,5,3[image]-truodothyramine] from plasma by erythrocytes. DPH was administered to rats in daily doses of 25 mg for 3 and 13 days, the bile duct was then cannulated, and L-T4 [thyroxine] was administered by intravenous injection. DPH produced an increased output of I131 in the bile of these rats, and the major 1131 compound in bile was T4 glu-curonide. Less radioactive iodide from T4 was excreted in the urine by these rats. DPH altered the metabolism of L-T4 in the isolated perfused rat liver. When DPH (25 mg) was added directly to blood perfusing the rat liver, the rate of disappearance of T4 from the blood was delayed somewhat, but the rate of accumulation of radioactive iodide in the blood was unaltered. The uptake of T4 by the liver proceeded more slowly and the output of I131 in the bile was greatly diminished. In other experiments the rats which were to be donors of blood or liver for the perfusion system were pretreated with daily 25-mt doses of DPH. Only in experiments in which all donors of blood and of first and second livers were treated with DPH for 11-13 days was the rate of disappearance of T4 from blood markedly increased. The uptake of T4 by the perfused liver was then greatly increased and an increased output of radioactive metabolites, chiefly T4 glucuro-nide, was found in bile. When DPH-4-C14 was added to the perfusing blood with the usual 25-mg dose of DPH, it was apparent that DPH was rapidly metabolized. As much as 76% of the dose was excreted in bile in 5 hr, chiefly as the glucuronide of 5-hydroxyphenyl-5[image]-phenyl-hy dantoin.