Abstract
1. SKL-13784, a novel series of 1-benzyl-4-aminoindole-based thyroid hormone receptor β (TRβ)-selective agonists, showed higher liver selectivity than GC-1 and was poorly distributed in the heart and brain. We aimed to clarify the mechanism of liver selectivity of SKL-13784 through a comparative study with GC-1.
2. Media-loss assays using fresh rat hepatocytes showed that the Oatp family may have been involved in liver uptake for both compounds and that SKL-13784 was more efficiently taken up than GC-1.
3. In addition, the media-loss assay results showed that hepatic uptake was important in eliminating both compounds in rats.
4. The low passive permeability of SKL-13784 on the parallel artificial membrane permeability assay (PAMPA) contributed to the limited distribution of SKL-13784 into extrahepatocytes.
5. Biliary extraction was a major route of SKL-13784 and GC-1 disposition. SKL-13784 was excreted into bile unchanged and in its glucuronide form, whereas almost all GC-1 in bile was in its glucuronide form. In bile duct-cannulated rats, a 4.3-fold decrease in t1/2 of SKL-13784 was observed, implicating enterohepatic biliary recirculation.
6. The selective distribution of SKL-13784 in the liver was largely due to efficient uptake via hepatic transporters.
Acknowledgements
The authors gratefully acknowledge Akiko Miyazaki, Hiroki Nagano and Satoko Yamaguchi for their assistance with the experiments, Koji Maeda for supplying SKL-13784 and GC-1 and Dr. Nobuhide Watanabe for his review of the manuscript and his suggestions.
Declaration of interest
The authors report no declarations of interest.