The effects of phenytoin (diphenylhydantoin) on the extrathyroidal turnover of thyroxine, 3,5,3'-triiodothyronine, 3,3',5'-triiodothyronine, and 3',5'-diiodothyronine in man.
The extrathyroidal metabolism of T4, T3, rT3, and 3',5'-diiodothyronine (3',5'-T2) was studied before and after treatment with 350 mg phenytoin (DPH) daily for 14 days in six hypothyroid patients receiving constant L-T4 replacement. The total and free serum concentrations of the four iodothyronines were reduced by approximately 30% during DPH treatment, whereas the free fractions in serum were unaltered. Concomitantly, serum TSH increased 137% (P less than 0.02). The production rate (PR) of T4 decreased 16% (P less than 0.005), indicating decreased intestinal absorption (bioavailability) of oral L-T4 during DPH treatment. The fractional rate of 5'-deiodination of T4 to T3 increased from 27% to 31% (P less than 0.05), whereas the rate of 5-deiodination of T4 to rT3 decreased from 45% to 25% (P less than 0.05). The urinary excretion of free and conjugated T4 was 2.3% of the T4 PR and was unaffected by DPH. Thus, the amount of T4 metabolized through nondeiodinative pathways apart from urinary excretion increased from 25% to 44% (P less than 0.05). The apparent distribution volume (Vd) of T4 increased (P less than 0.05), whereas the pool size was unchanged. The PR of T3 did not change during DPH treatment, nor did the mean transit time or the cellular clearance. The rT3 PR was reduced by 54% (P less than 0.02) during DPH treatment. Concomitantly, the transit time increased 10-fold (P less than 0.05), whereas Vd and pool size increased 5-fold (P less than 0.01 and P less than 0.05, respectively). The turnover of 3',5'-T2, in contrast to that of the other iodothyronines, did not change significantly during DPH treatment. T3 formation from T4 was measured in liver microsomal fractions from rats treated for 8 days with DPH and was almost identical to that in untreated animals. The data demonstrate that DPH in therapeutic concentrations did not affect serum protein binding of the iodothyronines. DPH reduced the intestinal absorption of T4 and increased the nondeiodinative metabolism of T4. The resulting decrease in total and free serum T4 and T3 was associated with an increase in serum TSH, demonstrating reduced negative feedback on the pituitary. Our data do not support the assumption that DPH induces increased hepatic deiodinating enzyme activity.(ABSTRACT TRUNCATED AT 400 WORDS)
D000368:Aged; D000818:Animals; D001711:Biotransformation; D004104:Diiodothyronines / Q000097:blood*; D005260:Female; D006801:Humans; D007037:Hypothyroidism / Q000097:blood* / Q000188:drug therapy; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D010672:Phenytoin / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013970:Thyronines / Q000097:blood*; D013974:Thyroxine / Q000097:blood* / Q000627:therapeutic use / Q000652:urine; D014284:Triiodothyronine / Q000097:blood* / Q000652:urine; D014285:Triiodothyronine, Reverse / Q000097:blood*
D004104:Diiodothyronines; D013970:Thyronines; D014284:Triiodothyronine; D014285:Triiodothyronine, Reverse; C030102:3',5'-diiodothyronine; D010672:Phenytoin; D013974:Thyroxine