title: Characterisation of liver-specific distribution of a novel 1-benzyl-4-aminoindole-based thyroid hormone receptor β agonist, SKL-13784: comparison with GC-1.
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.
authors.affiliation: a Drug Discovery Laboratories , Sanwa Kagaku Kenkyusho, Co., Ltd. , Mie , Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: a Drug Discovery Laboratories , Sanwa Kagaku Kenkyusho, Co., Ltd. , Mie , Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Izuchi
mesh_terms: D000085:Acetates / Q000493:pharmacokinetics*; D000818:Animals; D001646:Bile / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002853:Chromatography, Liquid; D020719:Glucuronides / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008314:Malonates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010636:Phenols / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry; D037042:Thyroid Hormone Receptors beta / Q000819:agonists*; D014018:Tissue Distribution
chemical_list: D000085:Acetates; C413355:GC 1 compound; D020719:Glucuronides; D007211:Indoles; D008314:Malonates; D010636:Phenols; C000595302:SKL-13784; D037042:Thyroid Hormone Receptors beta
keywords: Liver-specific distribution; liver transporters; low passive permeability; thyroid hormone receptor β agonist