Enterohepatic circulation of triiodothyronine (T3) in rats: importance of the microflora for the liberation and reabsorption of T3 from biliary T3 conjugates.

In normal rats, T3 glucuronide (T3G) is the major biliary T3 metabolite, but excretion of T3 sulfate (T3S) is greatly increased after inhibition of type I deiodinase, e.g. with 6-propyl-2-thiouracil (PTU). In this study, the fate of the T3 conjugates excreted with bile was studied to assess the significance of a putative enterohepatic circulation of T3 in rats. Conventional (CV) or intestine-decontaminated (ID) rats received iv [125I]T3G or [125I]T3S, the latter usually after pretreatment with PTU (1 mg/100 g BW). Radioactivity in plasma and bile or feces was analyzed by Sephadex LH-20 chromatography and HPLC. Within 1 h, 88% of injected T3G was excreted in bile of CV or ID rats, independent of PTU. About 75% of the injected T3S was excreted within 4 h in PTU-treated rats, in contrast to only 20% in controls. Up to 13 h after iv administration of T3G or T3S (+PTU) to intact ID and CV rats, fecal radioactivity consisted of more than 90% T3 in all CV rats, 95% of T3S in T3S-injected ID rats, and 30% T3 and 67% T3G in T3G-injected ID rats. In overnight-fasted CV rats injected with T3G, total plasma radioactivity rapidly declined until a nadir of 0.10% dose/ml at about 2.5 h, but radioactivity reappeared with a broad maximum of 0.12% dose/ml between 5.5-10 h. In the latter phase, plasma radioactivity consisted of predominantly I- and T3 in a ratio of 2:1. Reabsorption was diminished in fed CV rats and prevented in ID rats. Plasma T3 4-10 h after iv T3G injection to overnight-fasted CV rats was 12, 2, and 3 times higher than that in bile-diverted rats, fed CV rats, and ID rats, respectively, and similar to that 4 h after the injection of T3 itself. Total plasma radioactivity as well as plasma T3 6-13 h after iv administration T3S in PTU-treated rats were significantly increased in CV vs. ID rats, e.g. T3 0.016% vs. 0.005% dose/ml. These results demonstrate a significant enterohepatic circulation of T3 in rats in which bacterial hydrolysis of T3 conjugates excreted with bile plays an important role.