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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 µ M OCA, 100 µ M CDCA, or vehicle control for 72 hours followed by quantification of deuterated TCA uptake and efflux over time in Ca 2+ -containing and Ca 2+ -free conditions ( n = 3 donors). A mechanistic pharmacokinetic model was fit to the TCA mass-time data to obtain estimates for total uptake clearance (CL Uptake ), total intrinsic basolateral efflux clearance (CL int,BL ), and total intrinsic biliary clearance (CL int,Bile ). Modeling results revealed that FXR agonists significantly increased CL int,BL by &gt;6-fold and significantly increased CL int,Bile by 2-fold, with minimal effect on CL Uptake Immunoblotting showed that protein levels of the basolateral transporter subunits organic solute transporter α and β (OST α and OST β ) in FXR agonist-treated SCHH were significantly induced by &gt;2.5- and 10-fold, respectively. FXR agonist-mediated changes in the expression of other TCA transporters in SCHH were modest. In conclusion, this is the first report demonstrating that OCA and CDCA increased TCA efflux in SCHH, which contributed to reduced intracellular TCA concentrations. Increased basolateral efflux of TCA was consistent with increased OST α / β protein expression in OCA- and CDCA-treated SCHH.

the journal of pharmacology and experimental therapeutics/the journal of pharmacology and experimental therapeutics

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