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Propylthiouracil and Methimazole Display Contrasting Pathways of Peripheral Metabolism in Both Rat and Human^*

ALVIN TAUROG and MARTHA L. DORRIS

Department of Pharmacology, University of Texas Health Science Center Dallas, Texas 75235

Address all correspondence and requests for reprints to: Alvin Taurog, Ph.D., Department of Pharmacology, University of Texas Health Science Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235.

Abstract

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 β-glucuronidase led to the appearance of a ³⁵S-labeled compound less polar than MMI. In contrast, the major [³⁵S]PTU metabolite in bile (>50% of total ³⁵S) was completely converted to [³⁵S]PTU on incubation with β-glucuronidase and showed no conversion in a control incuDation. 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 β-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 β-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 (Endocrinology 122: 592–601,1988)

Footnotes

^* This work was supported by USPHS Grant AM-03612.

USPHS career research awardee.

Received July 8, 1987.