Propylthiouracil excretion

In contrast, methimazole is completely absorbed but at variable rates. It is readily accumulated by the thyroid gland and has a volume of distribution similar to that of propylthiouracil. Excretion is slower than with propylthiouracil 65-70% of a dose is recovered in the urine in 48 hours. 

Although several metaboUtes of propylthiouracil have been found (36,44), it is mainly excreted in urine as the glucuronide. Its relatively short plasma half-life requires that it be adniinistered four times daily. 

When 20 mg/kg of methimazole was administered i.p. or orally to rats, urinary methimazole glucuronides accounted for 36-48% of the dose in 24 hours. The only other urinary metabolite accounted for 10-20% and was not characterized. An additional 14-20% of methimazole was excreted unchanged in 24 hour urine. The bile contained methimazole glucuronide and two unidentified metabolites. One of which was the same as the unidentified urinary metabolites. Plasma proteins bound 5% of methimazole which had no affinity for any specific tissue. Methimazole had a much greater CHCI3/H2O partition coefficient and 1 0 solubility than did propylthiouracil. Between 77 and 95% of the methimazole was excreted in the urine and approximately 10% in the bile. Since fecal excretion was neglegible an enter-ohepatic circulation was present. The half life of urinary excretion was 5-7 hours regardless of the route of administration (15). 

Propylthiouracil is rapidly but incompletely absorbed after oral administration. It is metabolized in the liver with an elimination half-life of 1-2 hours. Carbimazole is absorbed rapidly and converted to methimazole, the active metabolite. Methimazole is metabolized in the liver and excreted in urine, less than 10% as unmetabolized methimazole. The elimination half-life of methimazole varies from 5 to 15 hours. Clinical responses are seen in 10-20 days but 2-10 weeks are needed for maximal inhibition. 

Propylthiouracil is rapidly absorbed, reaching peak serum levels after 1 hour. The bioavailability of 50-80% may be due to incomplete absorption or a large first-pass effect in the liver. The volume of distribution approximates total body water with accumulation in the thyroid gland. Most of an ingested dose of propylthiouracil is excreted by the kidney as the inactive glucuronide within 24 hours. 

Several reference compounds have been explored in the OECD endocrine disrupters programme, phenobarital and propylthiouracil being the most frequently studied (O Connor et al. 2002, Mellert et al. 2003, Cooke et al. 2004, Cho et al. 2003). The interpretation of positive findings in the rat concerning inhibition of thyroid function (which has been frequently found) presents considerable difficulty and there are many cases where such findings in rats have been shown to be of no relevance for the human (Akhtar et al. 1996, Waritz et al. 1996, Capen 1998, Poirier et al. 1999). Many drugs that act on thyroid function in rats share a mechanism of action based the induction of microsomal enzymes, which in turn may enhance the biliary excretion of thyroid hormones (Vansell and Klaassen 2001). 

S-Methylation is known for aromatic sidfhydryl groups such as thiophenols, 6-mercaptopurine and propylthiouracil, as well as for aliphatic thiols like captopril. Once formed, such methylthio metabolites can be further processed to sulfoxides and sulfones before being excreted. 

A metabohte of 17a-methyltestosterone, compound CLXXXII, has been reported to possess in the dog at doses below 1 mg/kg/day [406], more potent hypocholesterolemic activity than 17a-methyltestosterone. Compound CLXXXIII (SC-12,790) [407] has been found to possess as high oral hypocholesterolemic activity as androsterone given parenterally to rats rendered hypercholesterolemic with 6-propylthiouracil [408]. Substance CLXXXIII showed no effect on cholesterol biosynthesis from mevalonate in the liver, but enhanced cholesterol excretion in the bile of rats [409]. It is worthy of note that the 3jS-epimer of CLXXXIII was found to lack significant hypocholesterolemic activity even at doses as high as 10 mg/kg [407]. 

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