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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Disposition and Sterol-Lowering Effect of Ezetimibe in Multidrug Resistance-Associated Protein 2-Deficient Rats

Departments of Clinical Pharmacology (S.O., S.W., W.S.), Pharmacology (H.K.K., M.G.), and Biopharmaceutics and Pharmaceutical Technology (W.W.), University of Greifswald, Greifswald, Germany

Disposition of the lipid-lowering agent ezetimibe (EZ) and its glucuronide (GLUC), which is mainly formed by UDP-glucuronosyltransferase (UGT) 1A1, is influenced by the intestinal efflux transporters P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) 2. To evaluate the role of Mrp2 in overall disposition and pharmacodynamic effects of EZ, wild-type and Mrp2-deficient (TR-negative) Lewis.1W rats (eight males each) fed with a cholesterol-enriched diet were orally treated with 5 mg/kg EZ for 14 days. EZ and GLUC in serum, urine, and feces, and cholesterol, campesterol, and sitosterol in serum, were assayed using liquid chromatography (LC)-tandem mass spectrometry and LC-mass spectrometry methods, respectively. Gene expression of Bsep (bile salt exporting pump), multidrug resistance (Mdr) 1a, Mdr1b, Mrp2, Mrp3, Ntcp (sodium taurocholate co-transporting polypeptide), organic anion transporting polypeptides (Oatp) 1, 2, 4, and Ugt1a1 was quantified in several tissues using real-time reverse transcription-polymerase chain reaction. Mrp2 deficiency resulted in lower serum levels and fecal excretion of EZ (1.4 ± 0.4 versus 3.1 ± 1.1 ng/ml; 115 ± 48 versus 361 ± 102 µg/day, both p < 0.01), whereas serum concentrations of GLUC were manyfold increased compared with wild type (196 ± 76 versus 23 ± 25 ng/ml; p < 0.01), associated with elevated renal excretion and decreased intestinal clearance (7.8 ± 3.1 versus 0.4 ± 0.4 µg/day, p < 0.01; 0.3 ± 0.3 versus 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 expressed significantly higher 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 enterosystemic and enterohepatic recycling of the parent ezetimibe to the intestinal Niemann-Pick C 1-like 1 sterol-uptake compartment.

Address correspondence to: Stefan Oswald, Department of Clinical Pharmacology, Ernst Moritz Arndt University, Friedrich-Loeffler-Str. 23d, D-17487 Greifswald, Germany. E-mail: stefan.oswald{at}uni-greifswald.de

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