Rapid conversion of carbimazole to methimazole in serum; evidence for an enzymatic mechanism.
Carbimazole (CBZ) is one of the major drugs currently used for the treatment of Graves' disease. It is a carbethoxy derivative of methimazole (MMI), originally developed in the hope of obtaining a longer acting drug than methimazole. In the present study we have demonstrated that carbimazole is rapidly converted to methimazole in vitro by serum from rats and humans, and we have obtained evidence that this conversion is enzymatic. Experiments with [35S] CBZ in rats showed that the drug is so rapidly transformed to MMI after i.v. injection (within 3 min) that very little of the unchanged drug would be expected to reach the thyroid gland. The antithyroid action of CBZ in rats, therefore, can be ascribed entirely to the MMI to which it is rapidly converted. Although no experiments were performed with human subjects in vivo, the very rapid conversion of CBZ to MMI by human serum in vitro suggests that the antithyroid action of CBZ in humans can also be attributed to MMI. The original expectation of a longer acting drug has, therefore, not been met by CBZ. On the basis of the studies reported here there appears to be no advantage in using CBZ in preference to MMI for the treatment of Graves' disease. Although the in vivo action of CBZ must be attributed to its rapid conversion to MMI, the drug does possess inherent antithyroid activity. This was shown in the present study by the finding that CBZ is as potent as MMI in blocking thyroid peroxidase-catalysed iodination of thyroglobulin.
D000818:Animals; D002231:Carbimazole / Q000097:blood* / Q000494:pharmacology; D002854:Chromatography, Paper; D004798:Enzymes / Q000097:blood; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D007453:Iodide Peroxidase / Q000037:antagonists & inhibitors; D008297:Male; D008713:Methimazole / Q000097:blood*; D010664:Phenylmethylsulfonyl Fluoride / Q000494:pharmacology; D051381:Rats; D013053:Spectrophotometry; D013696:Temperature; D013997:Time Factors
D004798:Enzymes; D008713:Methimazole; D010664:Phenylmethylsulfonyl Fluoride; D002231:Carbimazole; D007453:Iodide Peroxidase