Research Articles
Synergistic influence of Abcb1 and Abcc2 on disposition and sterol lowering effects of ezetimibe in rats

https://doi.org/10.1002/jps.21821Get rights and content

Abstract

Pharmacokinetics of the sterol-lowering drug ezetimibe (EZ) is influenced by intestinal ABCB1 and ABCC2. This study in Lew.1W rats with “chemical” and genetic Abcb1 and Abcc2 deficiency was initiated to evaluate the individual contribution of both efflux carriers to the overall disposition and sterol-lowering effects of EZ. Disposition and sterol-lowering effects of EZ (5 mg/kg, 14 days) were measured in wild-type (WT) and Abcc2-deficient (Abcc2-) rats (N = 8 per group) and in animals treated with PSC833 (20 mg/kg) to generate “chemical” Abcb1-deficiency (Abcb1-, Abcb1-/Abcc2-). EZ serum levels decreased in the order WT (3.11 ± 1.09 ng/mL), Abcb1- (1.94 ± 1.10 ng/mL), Abcc2- (1.42 ± 0.42 ng/mL, p = 0.003 vs. WT), Abcb1-/Abcc2- (1.17 ± 0.53 ng/mL, p = 0.002 vs. WT) whereas the serum EZ glucuronide levels increased as follows: WT (23.2 ± 24.6 ng/mL), Abcb1- (119 ± 74.5 ng/mL, p = 0.002 vs. WT), Abcc2- (195±76.5 ng/mL, p < 0.001 vs. WT), Abcb1-/Abcc2- (676 ± 207 ng/mL, p < 0.001 vs. WT, Abcb1- and Abcc2-). Abcb1 and Abcc2 protein deficiency resulted synergistically in lower fecal but increased renal excretion of total EZ although to a much lower extent. The sterol-lowering effects of EZ were significantly correlated to serum levels of EZ. In conclusion, Abcb1 and Abcc2 deficiency leads to lower levels of the active EZ and in turn to decreased sterol-lowering effects. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:422–429, 2010

Section snippets

INTRODUCTION

Disposition and pharmacological effects of many drugs are markedly affected by the complex interplay between intestinal and hepatic metabolism and transport.1., 2., 3. One characteristic example is the frequently prescribed cholesterol-lowering drug ezetimibe which modulates the uptake of nutritional and biliary cholesterol via the intestinal Niemann Pick C 1 like 1 (NPC1L1) transporter.4 Major variables in disposition of ezetimibe in man are intestinal glucuronidation by enzymes of the

Animals

Male wild-type and Abcc2-deficient Lew.1W rats (250–350 g) were purchased from the Department of Pathophysiology (University of Greifswald, Germany) and hold under standard laboratory conditions in the life island box A 110 (Flufrance, Wissous, France) with mass-air displacement, (temperature 25°C, 12 h light–dark cycle with light on at 08.00 h a.m.). The animals had free access to acidified water and to a sterol enriched diet containing 16% fat, 1% cholesterol, 21% proteins and 0.5% sodium

RESULTS

In rats with “chemical” Abcb1-deficiency, ezetimibe trough serum concentrations 24 h after last administration on the 14th treatment day were numerically somewhat lower (1.94 ± 1.10 ng/mL vs. 3.11 ± 1.09 ng/mL, p = 0.093), whereas the glucuronide levels were about fivefold increased (119 ± 74.5 ng/mL vs. 23.2 ± 24.6 ng/mL, p < 0.001) compared to wild-type animals. Congenital Abcc2-deficiency led to significantly lower serum levels of ezetimibe by about 50% (1.42 ± 0.42 ng/mL, p = 0.003) and to

DISCUSSION

In this study was clearly shown that “chemical” deficiency of Abcb1 as induced by chronic treatment with PSC833 did not cause, as expected, increased serum concentrations of the parent ezetimibe. There was even a tendency for lower serum levels, also in Abcc2-deficient rats which were treated with PSC833. Congenital Abcc2-deficiency leads to significantly lower systemic ezetimibe exposure, whereas combined deficiency of Abcb1 and Abcc2 results in the lowest ezetimibe serum levels among all

CONCLUSIONS

Deficiency of Abcb1 and Abcc2 in rats leads to higher serum concentrations of ezetimibe glucuronide, lower levels of the active ezetimibe and in turn to a decreased sterol-lowering effect.

Acknowledgements

The authors are very grateful to Gitta Schumacher, Sabine Bade and Danilo Wegner for excellent technical assistance. The work was supported by the grants 01ZZ0403 (BMBF-NBL3) and 03IP612 (InnoProfile) of the German Federal Ministry for Education and Research.

REFERENCES (29)

  • T. Kosoglou et al.

    Ezetimibe: A review of its metabolism, pharmacokinetics and drug interactions

    Clin Pharmacokinet

    (2005)
  • S. Oswald et al.

    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

    Clin Pharmacol Ther

    (2006)
  • S. Oswald et al.

    Disposition of ezetimibe is influenced by polymorphisms of the hepatic uptake carrier OATP1B1

    Pharmacogenet Genomics

    (2008)
  • S. Oswald et al.

    Disposition and sterol-lowering effect of ezetimibe are influenced by single-dose coadministration of rifampin, an inhibitor of multidrug transport proteins

    Clin Pharmacol Ther

    (2006)
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