Effects of propylthiouracil on the biliary clearance of thyroxine (t4) in rats: Decreased excretion of 3,5,3′-triiodothyronine glucuronide and increased excretion of 3,3′,5′-triiodothyronine glucuronide and t4 sulfate

Abstract

The liver metabolizes t4 by deiodination and conjugation to t4 glucuronide (t4G), but little information exists about the formation of t4 sulfate (t4S) in vivo. We have examined the excretion of t4G, t4S, T4 and rT4 glucuronide (T4G and rT4G) in bile, collected under pentobarbital anesthesia 0,−8 h or 17−18 h after iv [125I]t4 injection to control and 6−propyl− 2−thiouracil (PTU)−treated rats. Radioactivity in bile, plasma, feces, and urine was analyzed by Sephadex LH−20 chromatography and HPLC. PTU induced a 2−fold increase in the biliary excretion of total radioactivity (26.6%. 15.0% dose between 0−8 h; 2.0%vs. 1.0% dose between 17−18 h). Biliary metabolites, 17−18 h after t4 injection, in control vs. PTU rats amounted to (percent dose): t4G, 0.44 us. 0.75; T4G, 0.19 vs. 0.07; rT4G, 0.02 vs. 0.15; and t4S, 0.06 vs. 0.32. Similar results were obtained for control rats when bile was collected between 7−8 h after iv t4. The excretion rate of T4G was lower and that of rT4G higher when bile was continuously collected for 8 h immediately after t4 administration, probably due to prolonged experimental stress. However, regardless of the period of bile collection, PTU induced a more than 24−fold decrease in the T4G/rT4G ratio and a 5−fold increase in t4S excretion. In the animals killed 18 h after t4 injection, PTU treatment increased plasma t4 retention by 50%, reduced urinary I" excretion by 74%, and increased fecal radioactivity by 47%. No conjugates were detected in feces, and the distribution of fecal t4:T4:rT4 was 70:18:2 in control and 68:7:6 in PTU−treated rats. The results indicate that 1) the glucuronidative clearance of t4 is not affected by PTU; 2) the T4G/rT4G ratio in bile is a sensitive indicator of type I deiodinase inhibition; 3) t4 undergoes significant sulfation in rats in vivo, and 4) biliary excretion of t4S is enhanced if its type I deiodination is inhibited. © 1989 by The Endocrine Society.