Research ArticlesSynergistic influence of Abcb1 and Abcc2 on disposition and sterol lowering effects of ezetimibe in rats
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.
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