EFFECTS OF 5,5'-DIPHENYLHYDANTOIN ON THE METABOLIC PATHWAY OF THYROID-HORMONE IN RATS

Treatment of rats with phenytoin (DPH), an anti-epileptic drug, result s in lower tissue thyroid hormone (TH) levels and interferes with the metabolic pathway of TH. To test the hypothesis that DPH affects the e nterohepatic cycle of TH and, thus, the kinetics of TH turnover, we pe rformed a kinetic experiment (three-compartment analysis) and a steady -state, double-isotope equilibrium experiment in rats treated for 3 we eks with DPH (50 mg/kg body weight per day) and in untreated controls, This included measurements of TH and TH metabolite levels, as well as the activities of enzymes involved in the TH metabolic pathway.DPH tr eatment resulted in a decrease in the production of thyroxine (T-4) (b y 25%) and triiodothyronine (T-3) (by 37%), a decrease in the T-3 conc entration in all three pools, and a redistribution of T-4 from the fas t to the slow pool. The amount of T-4 increased in intestinal contents and feces by 66% and 71% respectively. Expressed as a fraction of dai ly TH disposal, fecal loss of T-4 was enhanced from 10 to 23% and that of T-3 from 16 to 21%. An increase in T-4 and T-3 UDP-glucuronyltrans ferase activities was observed, suggesting that the increased fecal lo ss of T-4 and T-3 is secondary to an increased biliary output of their glucuronides. The reduced secretion of TH and increased fecal clearan ce during DPH treatment can lead in the long run to depletion of TH st ores.