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.
Footnotes
This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK068039]; the National Institutes of Health National Institute of Environmental Health Sciences [Grant ES006694]; the National Institutes of Health National Center for Complementary and Alternative Medicine [Grant AT002842]; and the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development [Grant HD062489]. The Liver Tissue Cell Distribution System was sponsored by the National Institutes of Health [Contract N01-DK70004/HHSN267200700004C].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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ABBREVIATIONS:
- NAFLD
- nonalcoholic fatty liver disease
- NASH
- nonalcoholic steatohepatitis
- EZE
- ezetimibe
- NPC1L1
- Niemann-Pick C1-like 1
- EZE-GLUC
- ezetimibe glucuronide
- ABC
- ATP-binding cassette
- MCD
- methionine and choline deficient
- HPLC
- high-performance liquid chromatography
- LC
- liquid chromatography
- MS/MS
- tandem mass spectrometry
- Mdr
- multidrug resistance
- Ugt
- UDP glucuronosyltransferase
- ERK
- extracellular signal-regulated kinase.
- Received June 8, 2011.
- Accepted November 23, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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