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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on June 13, 2006; DOI: 10.1124/jpet.106.104018

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Received for publication March 20, 2006.
Revised June 8, 2006.
Accepted for publication June 8, 2006.

Disposition and sterol-lowering effect of ezetimibe in multidrug resistance associated protein (Mrp) 2-deficient rats

Stefan Oswald 1*, Sabine Westrup 1, Markus Grube 2, Heyo K Kroemer 2, Werner Weitschies 3, Werner Siegmund 1

1 University of Greifswald, Department of Clinical Pharmacology 2 University of Greifswald, Department of Pharmacology 3 University of Greifswald, Department of Biopharmaceutics and Pharmaceutical Technology

* Address correspondence to: E-mail: stefan.oswald{at}uni-greifswald.de

Abstract

Disposition of the lipid lowering agent ezetimibe (EZ) and its glucuronide (GLUC) which is mainly formed by UGT1A1 is influenced by the intestinal efflux transporters P-glycoprotein (P-gp) and MRP2. To evaluate the role of Mrp2 in overall disposition and pharmacodynamic effect of EZ, wild-type and Mrp2-deficient TR-negative Lew.1W rats (each 8 males) fed with a cholesterol-enriched diet were orally treated with 5 mg/kg EZ for 14 days. EZ and GLUC in serum, urine, feces and organ tissue and cholesterol, campesterol and sitosterol in serum were assayed using LC-MS/MS and LC-MS methods, respectively. Gene expression of Bsep, Mdr1a, Mdr1b, Mrp2, Mrp3, Ntcp, Oatp1, 2, 4 and Ugt1a1 was quantified in several tissues using real-time RT-PCR (TaqMan®). Mrp2-deficiency resulted in lower serum levels and fecal excretion of EZ (1.4±0.4 vs. 3.1±1.1 ng/ml; 115±48 vs. 361±102 µg/d, both p<0.01) whereas serum concentrations of GLUC were manifold increased compared to wild-type (196±76 vs. 23±25 ng/ml; p<0.01) associated with elevated renal excretion and decreased intestinal clearance (7.8±3.1 vs. 0.4±0.4 µg/d, p<0.01; 0.3±0.3 vs. 15±17 ml/min; p<0.05). The sterol-lowering effect of EZ was reduced in correlation to EZ serum levels (cholesterol r=0.449, p=0.093; campesterol r=0.717, p=0.003; sitosterol r=0.507, p=0.054) whereas GLUC was inversely correlated (r=-0.743, p=0.002; r=-0.768, p=0.001; r=-0.634, p=0.011). Disposition of EZ may have been additionally influenced by hepatic P-gp, Mrp3 and Ugt1a1 which were significantly higher expressed in Mrp2-deficient rats. Mrp2-deficiency in rats is associated with decreased sterol-lowering effect of ezetimibe obviously caused by lower intestinal clearance of the glucuronide and decreased entero-systemic and entero-hepatic recycling of the parent ezetimibe to the intestinal NPC1L1 sterol-uptake compartment.


Key words: Ezetimibe, Mrp2, P-glycoprotein (P-gp), Ugt1a1, disposition, drug transporters


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