Thyroid and liver trophic changes in rats secondary to liver microsomal enzyme induction caused by an experimental leukotriene antagonist (L-649,923).

Thyroid hyperplasia and/or hepatomegaly were observed in a 14-week oral toxicity study with L-649,923, a leukotriene antagonist, at doses of 50 and 150 mg/kg/day. In a 16-day study, L-649,923 caused an increase in plasma TSH and hepatic enzyme induction, but did not affect plasma T3 and T4 levels. Light microscopy and ultrastructural examination of the liver and thyroid showed changes indicative of hepatic enzyme induction and increased stimulation of the thyroid by TSH. Because other hepatic enzyme inducers cause thyroid hyperplasia by increasing the turnover of plasma T3 and T4 it was hypothesized that L-649,923-induced thyroid hyperplasia might be occurring by the same mechanism. To examine this theory, rats were treated po with 300 mg/kg/day of L-649,923 for 17 days. On Day 15, all rats were dosed iv with [125I]thyroxine (33 microCi/rat). At various times after dosing, blood was collected and plasma levels of 125I were determined. The clearance and elimination rate constant were significantly larger in treated animals than in the control group (p less than 0.01). This work demonstrates that L-649,923 increases the plasma turnover of thyroxine which is associated with a stimulation of TSH and thyroid hyperplasia.