Farnesoid X Receptor Agonists Obeticholic Acid and Chenodeoxycholic Acid Increase Bile Acid Efflux in Sandwich-Cultured Human Hepatocytes: Functional Evidence and Mechanisms

The Journal of Pharmacology and Experimental Therapeutics
Cen GuoKim L Brouwer

Abstract

The farnesoid X receptor (FXR) is a nuclear receptor that regulates genes involved in bile acid homeostasis. FXR agonists, obeticholic acid (OCA) and chenodeoxycholic acid (CDCA), increase mRNA expression of efflux transporters in sandwich-cultured human hepatocytes (SCHH). This study evaluated the effects of OCA and CDCA treatment on the uptake, basolateral efflux, and biliary excretion of a model bile acid, taurocholate (TCA), in SCHH. In addition, changes in the protein expression of TCA uptake and efflux transporters were investigated. SCHH were treated with 1 µM OCA, 100 µM CDCA, or vehicle control for 72 hours followed by quantification of deuterated TCA uptake and efflux over time in Ca2+-containing and Ca2+-free conditions (n = 3 donors). A mechanistic pharmacokinetic model was fit to the TCA mass-time data to obtain estimates for total uptake clearance (CLUptake), total intrinsic basolateral efflux clearance (CLint,BL), and total intrinsic biliary clearance (CLint,Bile). Modeling results revealed that FXR agonists significantly increased CLint,BL by >6-fold and significantly increased CLint,Bile by 2-fold, with minimal effect on CLUptake Immunoblotting showed that protein levels of the basolateral transporter subunits ...Continue Reading

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Citations

Apr 16, 2020·Toxicological Sciences : an Official Journal of the Society of Toxicology·James J BeaudoinKim L R Brouwer
Apr 6, 2020·Pharmacology & Therapeutics·James J BeaudoinMelina M Malinen
Jul 28, 2021·Advanced Drug Delivery Reviews·Virender KumarRam I Mahato
Nov 28, 2018·Molecular Pharmaceutics·Melina M MalinenKim L R Brouwer
Sep 24, 2021·Alimentary Pharmacology & Therapeutics·Benedikt SimbrunnerThomas Reiberger
Oct 3, 2021·Molecular Pharmacology·William A MurphyKim L R Brouwer

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