Methimazole pharmacology in the rat: Studies using a newly developed radioimmunoassay for methimazole

Methimazole [l-methyl-2-mercaptoimidazole (MMI)] was given to normal male rats in their drinking water in concentrations ranging from 0.0001-0.05% for either 1 week or 1 month. Serum MMI levels in the rats ranged from 0.008-19.6 µg/ml, and were similar after 1 week and 1 month of treatment. Serum MMI was linearly related to the MMI concentration in the drinking water (r = 0.98, P < 0.001). In contrast, intrathyroid MMI content plateaued with increasing MMI concentrations in the water, and was linearly related to the logarithm of the MMI concentration. At the highest MMI concentration (0.05%), thyroid MMI contents were similar in the 1- week and 1-month groups (-1 × 10^-4 M). Surprisingly, at lower MMI concentrations, thyroid MMI content was significantly higher in the 1-week group than the 1-month group. Thyroid function was inhibited by MMI with similar depression of serum T₄ or T₃ after 1 week or 1 month of MMI treatment. Although the MMI concentration for 50% suppression of thyroid PBI was 0.003% in both groups, thyroid MMI content at this MMI concentration was 97 µM after 1 week but only 15 µM after 1 month. The continued thyroid-inhibiting activity of MMI at 1 month, despite a striking decrease in thyroid MMI content, may relate to intrathyroid iodide depletion, which was more severe after 1 month (thyroid ¹²⁷I = 40 µM) than after 1 week (thyroid ¹²⁷I = 140 µM.) or in controls (470 µM). Rats were given 0.05% MMI for either 1 week or 1 month, and the drug was then withdrawn. In the 1-week group, serum MMI disappeared biexponentially, with a rapidly declining phase (t_1/2 = 3.2 h) and a second, slower disappearance phase (t_1/2 = 47.7 h). Similar findings were noted after 1 month of treatment. The disappearance of thyroid MMI was also biexponential after 1 week, but this variable could not be evaluated after 1 month because thyroid MMI fell rapidly to undetectable levels. There was a highly significant correlation in the 1-week group between the disappearance of MMI from the thyroid and the recovery of thyroid function as assessed by thyroid PBI (r = 0.81, P < 0.01). Despite the very rapid disappearance of MMI from the thyroid after 1 month of treatment, the recovery time of thyroid PBI was significantly longer than after 1 week of treatment (2.1 days vs. 1.4 days for 50% recovery, P < 0.01). This difference may relate to the effects of severe iodide depletion after 1 month of MMI treatment, as well as altered MMI metabolism in this setting.