Propylthiouracil and methimazole display contrasting pathways of peripheral metabolism in both rat and human

We have developed HPLC procedures for analyzing the metabolites of [35S]methylmercaptoimidazole [( 35S] MMI) and [35S]propylthiouracil [( 35S]PTU) in bile, urine, serum, and liver of rats. We also studied urinary metabolites of [35S] MMI and [35S]PTU in one human subject. In bile collected from [35S]MMI-injected rats, two major metabolites accounted for 80-90% of the total 35S. Incubation of these metabolites either with or without beta-glucuronidase led to the appearance of a 35S-labeled compound less polar than MMI. In contrast, the major [35S]PTU metabolite in bile (greater than 50% of total 35S) was completely converted to [35S]PTU on incubation with beta-glucuronidase and showed no conversion in a control incubation. From these results we conclude that the major biliary metabolites of MMI in rats are not glucuronides. They appear to be labile conjugates of a metabolite of MMI. After [35S]MMI injection into rats, two major and at least four minor metabolites were observed in urine. In one human who received [35S]MMI orally, the HPLC profile of 35S in urine was similar to that of the rat. Incubation of human urine or of its isolated major component with beta-glucuronidase had no significant effect on the HPLC profile. On the other hand, the major urinary metabolite of [35S]PTU in human and rat urine was completely converted to [35S]PTU on incubation of whole urine with beta-glucuronidase. These results indicate that glucuronides comprise at most only a minor fraction of MMI metabolites in urine of rats or humans. Based on similarities in elution time, the metabolites of [35S]PTU in urine closely resembled those in bile of rats. In contrast, the metabolites of [35S]MMI in urine were strikingly different from those in bile. PTU displays noncovalent binding to serum protein to a much greater extent than does MMI. However, after injection of [35S]MMI into rats, a significant fraction of the 35S was firmly bound to protein in both serum and liver. This binding appeared to be covalent and involved metabolism of [35S]MMI. This type of binding was much less detectable after the injection of [35S]PTU into rats.