Molecular mechanism of altered ezetimibe disposition in nonalcoholic steatohepatitis
Language: 
English
Abstract: 

Ezetimibe (EZE) lowers serum lipid levels by blocking cholesterol uptake in the intestine. Disposition of EZE and its pharmacologically active glucuronide metabolite (EZE-GLUC) to the intestine is dependent on hepatobiliary efflux. Previous studies suggested that hepatic transporter expression and function may be altered during nonalcoholic steatohepatitis (NASH). The purpose of the current study was to determine whether NASH-induced changes in the expression and function of hepatic transporters result in altered disposition of EZE and EZE-GLUC. Rats fed a methionine- and choline-deficient (MCD) diet for 8 weeks were administered 10 mg/kg EZE either by intravenous bolus or oral gavage. Plasma and bile samples were collected over 2 h followed by terminal urine and tissue collection. EZE and EZE-GLUC concentrations were determined by liquid chromatography-tandem mass spectrometry. The sinusoidal transporter Abcc3 was induced in MCD rats, which correlated with increased plasma concentrations of EZE-GLUC, regardless of dosing method. Hepatic expression of the biliary transporters Abcc2 and Abcb1 was also increased in MCD animals, but the biliary efflux of EZE-GLUC was slightly diminished, whereas biliary bile acid concentrations were unaltered. The cellular localization of Abcc2 and Abcb1 appeared to be internalized away from the canalicular membrane in MCD livers, providing a mechanism for the shift to plasma drug efflux. The combination of induced expression and altered localization of efflux transporters in NASH shifts the disposition profile of EZE-GLUC toward plasma retention away from the site of action. This increased plasma retention of drugs in NASH may have implications for the pharmacological effect and safety of numerous drugs.

Author(s): 
Hardwick, Rhiannon N.
Fisher, Craig D.
Street, Stephanie M.
Canet, Mark J.
Cherrington, Nathan J.
Item Type: 
Journal Article
Publication Title: 
Drug Metabolism and Disposition: The Biological Fate of Chemicals
Journal Abbreviation: 
Drug Metab. Dispos.
Publication Date: 
Mar 2012
Publication Year: 
2012
Pages: 
450-460
Volume: 
40
Issue: 
3
ISSN: 
1521-009X
DOI: 
10.1124/dmd.111.041095
Library Catalog: 
NCBI Published Medical (?)
Extra: 
PMID: 22112382 PMCID: PMC3286272

Turabian/Chicago Citation

Rhiannon N. Hardwick, Craig D. Fisher, Stephanie M. Street, Mark J. Canet and Nathan J. Cherrington. Mar 2012. "Molecular mechanism of altered ezetimibe disposition in nonalcoholic steatohepatitis." Drug Metabolism and Disposition: The Biological Fate of Chemicals 40: 3: 450-460. 10.1124/dmd.111.041095.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1124/dmd.111.041095 | issn = 1521-009X | volume = 40 | pages = 450-460 | last = Hardwick | first = Rhiannon N. | coauthors = Fisher, Craig D., Street, Stephanie M., Canet, Mark J., Cherrington, Nathan J. | title = Molecular mechanism of altered ezetimibe disposition in nonalcoholic steatohepatitis | journal = Drug Metabolism and Disposition: The Biological Fate of Chemicals | date = Mar 2012 | pmid = | pmc = }} </ref>