Intestinal expression of P-glycoprotein (ABCB1), multidrug resistance associated protein 2 (ABCC2), and uridine diphosphate-glucuronosyltransferase 1A1 predicts the disposition and modulates the effects of the cholesterol absorption inhibitor ezetimibe in humans

Clinical Pharmacology and Therapeutics
S OswaldW Siegmund

Abstract

Ezetimibe is an inhibitor of the cholesterol uptake transporter Niemann-Pick C1-like protein (NPC1L1). Target concentrations can be influenced by intestinal uridine diphosphate-glucuronosyltransferases (UGTs) and the efflux transporters P-glycoprotein (P-gp) (ABCB1) and multidrug resistance associated protein 2 (MRP2) (ABCC2). This study evaluates the contribution of these factors to the disposition and cholesterol-lowering effect of ezetimibe before and after induction of UGT1A1, P-gp, and MRP2 with rifampin (INN, rifampicin). Serum concentrations of ezetimibe, as well as its glucuronide, and the plant sterols campesterol and sitosterol (surrogate for cholesterol absorption) were studied in 12 healthy subjects before and after rifampin comedication. In parallel, duodenal expression of UGT1A1, P-gp, MRP2, and NPC1L1 was quantified by use of real-time reverse transcriptase-polymerase chain reaction and quantitative immunohistochemical evaluation. The affinity of ezetimibe and its glucuronide to P-gp and MRP2 was assessed in P-gp- overexpressing Madin-Darby canine kidney II cells and P-gp-containing or MRP2-containing inside-out vesicles. Up-regulation of intestinal P-gp, MRP2, and UGT1A1 (but not of NPC1L1) by rifampin was assoc...Continue Reading

Citations

Jun 23, 2009·Acta Pharmacologica Sinica·Alice Cristina RodriguesRosario Dominguez Crespo Hirata
Aug 7, 2008·Proceedings of the National Academy of Sciences of the United States of America·Adam B WeinglassMaria L Garcia
Apr 7, 2010·Expert Opinion on Drug Metabolism & Toxicology·Alice C Rodrigues
Jun 2, 2007·Expert Opinion on Drug Metabolism & Toxicology·Mary Ellen Sweeney, Rebecca R Johnson
Jan 20, 2010·Drug Metabolism Reviews·Katalin JemnitzPeter Krajcsi
Oct 31, 2007·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·S OswaldH K Kroemer
Sep 9, 2008·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Sanna SiissaloAnn Marie Kaukonen
Sep 11, 2007·Journal of Pharmaceutical Sciences·Stefan OswaldWerner Siegmund
May 31, 2018·Expert Opinion on Drug Metabolism & Toxicology·Karina Cunha E RochaAlice Cristina Rodrigues
Mar 14, 2007·Current Opinion in Lipidology·Gerd SchmitzPeter Ugocsai
May 10, 2008·European Journal of Gastroenterology & Hepatology·Stephen R RitchiePeter N Black
Apr 18, 2009·British Journal of Clinical Pharmacology·Jurij TronteljAles Mrhar
Dec 17, 2009·Naunyn-Schmiedeberg's Archives of Pharmacology·Monica VennerWerner Siegmund
Jun 14, 2008·Pharmacogenetics and Genomics·Stefan OswaldWerner Siegmund
Dec 24, 2010·British Journal of Clinical Pharmacology·Michael DerksMary Phelan
Mar 30, 2007·Clinical Pharmacology and Therapeutics·U I SchwarzW Kirch
Mar 29, 2018·Current Medicinal Chemistry·Silvina VillanuevaMary Vore
Jan 19, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Frederik WeißOliver Poetz
Dec 19, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Maciej J Zamek-GliszczynskiAleksandra Galetin
May 16, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Dirk R de WaartRonald P J Oude Elferink
Jun 15, 2006·The Journal of Pharmacology and Experimental Therapeutics·Stefan OswaldWerner Siegmund
May 21, 2013·Pharmacological Reviews·Jörg KönigMartin F Fromm
Feb 24, 2012·Pharmacological Reports : PR·Dariusz SuchyBogusław Okopień
Mar 24, 2020·British Journal of Pharmacology·Pablo Torres-VergaraJeffrey Penny
Nov 16, 2007·The Journal of Biological Chemistry·María Fabiana De RosaClifford Lingwood
May 28, 2020·Clinical Pharmacology and Therapeutics·Maciej J Zamek-GliszczynskiAleksandra Galetin
Jun 15, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Takehito YamamotoHiroshi Suzuki
Nov 22, 2018·Journal of Pharmaceutical Health Care and Sciences·Satsuki HashimotoYoshimichi Sai
Jul 21, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Andrew J LickteigNathan J Cherrington
Jul 3, 2019·Surgery for Obesity and Related Diseases : Official Journal of the American Society for Bariatric Surgery·Célia Lloret-LinaresXavier Declèves

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antimicrobial Resistance (ASM)

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Antimicrobial Resistance

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.