METHIMAZOLE PHARMACOLOGY IN THE RAT - STUDIES USING A NEWLY DEVELOPED RADIOIMMUNOASSAY FOR METHIMAZOLE

Methimazole [1-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 wk or 1 mo. Serum MMI levels in the rats ranged from 0.008-19.6 .mu.g/ml, and were similar after 1 wk and 1 mo. 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 wk and 1 mo. groups (.apprx. 1 .times. 10-4 M). Surprisingly, at lower MMI concentrations, thyroid MMI content was significantly higher in the 1 wk group than the 1 mo. group. Thyroid function was inhibited by MMI with similar depression of serum T4 [thyroxine] or T3 [triiodothyronine] after 1 wk or 1 mo. of MMI treatment. Although the MMI concentration for 50% suppression of thyroid PBI [protein-bound iodine] was 0.003% in both groups, thyroid MMI content at this MMI concentration was 97 .mu.M after 1 wk, but only 15 .mu.M after 1 mo. The continued thyroid-inhibiting activity of MMI at 1 mo., despite a striking decrease in thyroid MMI content, may relate to intrathyroid I depletion, which was more severe after 1 mo. (thyroid 127I = 40 .mu.M) than after 1 wk (thyroid 127I = 140 .mu.M) or in controls (470 .mu.M). Rats were given 0.05% MMI for either 1 wk or 1 mo., and the drug was then withdrawn. In the 1 wk group, serum MMI disappeared biexponentially, with a rapidly declining phase (t1/2 = 3.2 h) and a 2nd, slower disappearance phase (t1/2 = 47.7 h). Similar findings were noted after 1 mo. of treatment. The disappearance of thyroid MMI was also biexponential after 1 wk, but this variable could not be evaluated after 1 mo. because thyroid MMI fell rapidly to undetectable levels. There was a highly significant correlation in the 1 wk 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 mo. of treatment, the recovery time of thyroid PBI was significantly longer than after 1 wk of treatment (2.1 days vs. 1.4 days for 50% recovery, P < 0.01). This difference may related to the effects of severe I depletion after 1 mo. of MMI treatment, as well as altered MMI metabolism in this setting.