Combined phenytoin and salicylate effects on thyroid function tests

To evaluate the effects of salicylates (ASA) on thyroid function tests (TFT's) in patients already taking phenytoin (DPH), 6 adults received a daily dose of DPH to achieve a steady state serum DPH. ASA was then added stepwise (325, 650, 975 mg q 4hr) at 2-day intervals. TFTs, total serum and free salivary DPH were measured. Therapeutic steady state phenytoin levels caused a significant decrease in serum free thyroxine (FT4), total T4, total T3 (TT3) and a significant but slight increase in T3RU. The TSH remained normal. When ASA was co-administered with DPH, the serum free DPH increased, the total T4, TT3, FT4 significantly decreased further, and the T3RU significantly declined toward pre-treatment levels. The decrease of FT4 was in contrast to the increase in FT4 known to occur with ASA alone. Despite the decline in total T4, TT3, and FT4, the TSH remained normal. In conclusion, when ASA is co-administered with DPH, further alterations in TFTs occur which require cautious interpretation. Our in vivo and in vitro data show that these changes are consistent with ASA-induced displacement of T4 from its binding proteins and DPH-induced clearance of FT4.