METHIMAZOLE PHARMACOLOGY IN MAN - STUDIES USING A NEWLY DEVELOPED RADIOIMMUNOASSAY FOR METHIMAZOLE

A radioimmunoassay for the antithyroid drug methimazole [1-methyl-2-mercaptoimidazole (MMI)] was developed. A MMI derivative, 5-COOH-MMI, was conjugated to porcine thyroglobulin, and antibodies to the conjugate were raised in rabbits. [35S]MMI was used as the tracer. At a final antibody dilution of 1:100, the assay could detect MMI in amounts as low as 2.5 ng. The putative MMI metabolites 3-methyl-2-thiohydantoin and 1-methylimidazole had minor cross-reactivities of 2.1% and 0.5%, respectively. There was no effect of serum proteins on MMI immunoactivity. MMI was given orally to normal subjects (6), hyperthyroid patients (5), patients with hepatic cirrhosis (4), and normal lactating women (4). After a single dose of 60 mg, peak MMI levels were similar in the normal subjects and the hyperthyroid patients (.apprx. 1.5 .mu.g/ml). Patients with hepatic cirrhosis had similar peak MMI serum levels [1.31 .+-. 0.3 (.+-. SEM) .mu.g/ml], but the half-time of MMI disappearance from serum was significantly prolonged compared with the normal value (21.2 vs. 6.0 h; P < 0.001). The lactating women received 40 mg MMI as a single dose. Over the next 8 h, mean MMI levels in serum and milk were nearly identical, with a mean serum to milk ratio of 1.03 .+-. 0.16. A total of 70.0 .+-. 6.0 .mu.g MMI was excreted in the milk over the 8 h time period. This amount of MMI could affect neonatal thyroid function.