Biliary excretion of 35S-labelled propylthiouracil, methimazole and carbimazole in untreated and pentobarbitone pretreated rats

Abstract The excretion of 35 S-labelled antithyroid drugs 4(6)-Propyl-2-thiouracil (PTU), methimazole and carbimazole in the bile of the rat was studied. Carbimazole had the highest biliary clearance and PTU the lowest. The total amount of 35 S-radioactivity excreted in the bile 5 hr after the i.v. injection of the drugs was 31·71 ± 8·16 per cent (mean ± S.E.) of the dose for carbimazole, 21·10 ± 2·80 per cent for methimazole and 8·20 ± 0·62 per cent for PTU in rats not pretreated with pentobarbitone. The nature of the 35 S-compounds excreted in the bile was investigated using thinlayer chromatography. Methimazole and carbimazole gave the same number of metabolites and with exactly the same R f s in four different solvent systems. 10·60 per cent of 35 S-radioactivity in the bile of rats injected with methimazole was due to free methimazole; about the same percentage of free methimazole was observed after carbimazole injection. There was no free carbimazole detectable in the bile. These findings suggest that carbimazole is metabolized through methimazole. None of the metabolites of the three drugs which appeared in the bile had R f similar to free thiourea or to conjugates of thiourea appearing in the bile of rats injected with [ 35 S]thiourea. It is concluded that hepatic metabolism of the three drugs does not occur through thiourea. The major metabolite of methimazole in the bile was a glucuronic acid conjugate hydrolysed by β-glucuronidase to a metabolite different from methimazole. The main metabolite of PTU was also a glucuronic acid conjugate which was hydrolysed by β-glucuronidase to a compound having the same R f s as free PTU in four different solvent systems. It is concluded that while methimazole is conjugated with glucuronic acid in the liver of the rat after previous conversion to another compound, PTU is itself conjugated with glucuronic acid. A marked increase in the biliary excretion of 35 S-radioactivity occurred in rats injected with [ 35 S]methimazole and pretreated with pentobarbitone. The amount of radioactivity excreted in the bile within 5 hr after the injection was increased more than 100 per cent. The biliary clearance rate (BRC) and the bile/plasma ratio (B/P ratio) of the radioactivity were also significantly increased by the barbiturate. This was due mainly to increased biliary excretion of the glucuronide of methimazole. The effect of pentobarbitone on carbimazole was similar although less marked. The BCR of [ 35 S]PTU was also enhanced by pentobarbitone. This was due, however, solely to significantly higher biliary flow in the pretreated with pentobarbitone rats. The B/P ratio of radioactivity was not increased by the barbiturate.