The effect of diphenylhydantoin on thyroxine metabolism in man

The effect of 5,5'-diphenylhydantoin on thyroxine metabolism was examined in five normal volunteers. Intravenous injection of radiothyroxine was followed by a 10-12 day control and subsequent 9-14 day treatment periods. During oral administration of diphenylhydantoin, plasma thyroxine concentration decreased to about 80% of its pretreatment level and the plasma radiothyroxine disappearance rate increased a maximum of 20% over control estimates. These changes were a result of increases in both urinary and fecal excretion of radioisotope.A minimum plasma thyroxine was apparent after 10-12 days of diphenylhydantoin administration. In two of the subjects, treatment was sufficiently prolonged to achieve this new steady state. In these subjects, the decrease in total body thyroxine was balanced by the increase in the fractional turnover rate. As a result, absolute thyroxine degradation during diphenylhydantoin administration was unchanged from the pretreatment values. Plasma ultrafiltration was used to estimate the free thyroxine fraction at regular intervals during the control and treatment periods. During diphenylhydantoin treatment, there was little or no change in this fraction and therefore, absolute free thyroxine decreased. Thyroxine-binding globulin and thyroxine-binding prealbumin capacities remained constant. These results indicate that thyroxine degradation can proceed at a normal rate in subjects receiving diphenylhydantoin despite decreases in plasma free thyroxine concentration. If free thyroxine is the only portion of the hormone available for cellular utilization, then free thyroxine clearance must be increased in these subjects. This increase in clearance could represent either a direct stimulation of peripheral thyroxine metabolism by diphenylhydantoin, or it could reflect the response of intrinsic regulatory systems to a diphenylhydantoin-mediated displacement of thyroxine from thyroxine-binding globulin. Whatever the mechanism for this effect, a decreased free thyroxine value in patients receiving diphenylhydantoin may not imply hypothyroidism.