ABSTRACT
1. SKL-13784, a novel series of 1-benzyl-4-aminoindole-based thyroid hormone receptor ß (TRß)-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.
