Hepatic Transporter Alterations by Nuclear Receptor Agonist T0901317 in Sandwich-Cultured Human Hepatocytes: Proteomic Analysis and PBPK Modeling to Evaluate Drug-Drug Interaction Risk.

The Journal of Pharmacology and Experimental Therapeutics
Katsuaki ItoKim L R Brouwer

Abstract

In vitro approaches for predicting drug-drug interactions (DDIs) caused by alterations in transporter protein regulation are not well established. However, reports of transporter regulation via nuclear receptor (NR) modulation by drugs are increasing. This study examined alterations in transporter protein levels in sandwich-cultured human hepatocytes (SCHH; n = 3 donors) measured by liquid chromatography-tandem mass spectrometry-based proteomic analysis after treatment with N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide (T0901317), the first described synthetic liver X receptor agonist. T0901317 treatment (10 μM, 48 hours) decreased the levels of organic cation transporter (OCT) 1 (0.22-, 0.43-, and 0.71-fold of control) and organic anion transporter (OAT) 2 (0.38-, 0.38-, and 0.53-fold of control) and increased multidrug resistance protein (MDR) 1 (1.37-, 1.48-, and 1.59-fold of control). The induction of NR downstream gene expression supports the hypothesis that T0901317 off-target effects on farnesoid X receptor and pregnane X receptor activation are responsible for the unexpected changes in OCT1, OAT2, and MDR1. Uptake of the OCT1 substrate metformin in SCHH was decrease...Continue Reading

References

May 4, 2000·Toxicology in Vitro : an International Journal Published in Association with BIBRA·E L LeCluyseJ H Hochman
Nov 23, 2000·Genes & Development·J R SchultzB Shan
Dec 20, 2003·Current Topics in Medicinal Chemistry·Raju Mohan, Richard A Heyman
Jan 27, 2006·The Journal of Pharmacology and Experimental Therapeutics·Michael SaborowskiJyrki J Eloranta
Jul 5, 2007·Clinical Pharmacology and Therapeutics·Y ShuK M Giacomini
Dec 31, 2009·Cancer Chemotherapy and Pharmacology·Stefan HarmsenJ H M Schellens
Jun 23, 2012·Pharmacogenetics and Genomics·Li GongTeri E Klein
Jan 22, 2013·Drug Metabolism Reviews·Jeff L StaudingerWenqi Cui
Apr 17, 2013·Clinical Pharmacology and Therapeutics·K L R BrouwerUNKNOWN International Transporter Consortium
Jun 13, 2013·Molecular & Cellular Proteomics : MCP·Ruedi AebersoldRalph A Bradshaw
Nov 13, 2014·Current Topics in Medicinal Chemistry·Andrea CarottiAntonio Macchiarulo
Mar 29, 2016·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·H J BurtK Rowland-Yeo
Aug 21, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Li WangJashvant D Unadkat
Aug 23, 2016·Expert Opinion on Drug Metabolism & Toxicology·David E Amacher
Sep 28, 2016·Current Issues in Molecular Biology·Zhiqiang MaDongjin Wang
Dec 3, 2016·Nature Reviews. Drug Discovery·Rita SantosJohn P Overington
Dec 13, 2016·Journal of Pharmaceutical Sciences·Bhagwat PrasadDeepak Kumar Bhatt
Apr 6, 2017·Clinical Pharmacology and Therapeutics·Eio SundelinN Jessen
Jul 18, 2018·International Journal of Molecular Sciences·Chang Yeob Han
Jan 28, 2019·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Melina M MalinenKim L R Brouwer
Jun 4, 2019·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Camilla BernasconiSandra Coecke

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Citations

May 7, 2021·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Xian-Mei SongRui-Feng Liang

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