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Journal of Lipid Research, Vol. 50, 1463-1471, July 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Patient-Oriented and Epidemiological Research

Effects of ezetimibe and simvastatin on apolipoprotein B metabolism in males with mixed hyperlipidemia

André J Tremblay^*,, Benoît Lamarche^*,, Jean-Charles Hogue^*, and Patrick Couture^1,*,

^* Lipid Research Center, CHUL Research Center, Québec City, Québec, Canada
Institute on Nutraceuticals and Functional Foods, Laval University, Québec City, Québec, Canada

This work is supported by an unrestricted research grant from Merck Frosst/Schering Company; a scholarship from Fonds de recherche en santé du Québec (P.C.); and a grant from the Heart and Stroke Foundation (J-C.H.). Benoît Lamarche is a Canada Research Chair in Nutrition and Cardiovascular Health.

Published, JLR Papers in Press, March 22, 2009.

¹ To whom correspondence should be addressed. e-mail: patrick.couture{at}crchul.ulaval.ca

Sixteen hyperlipidemic men were enrolled in a randomized, placebo-controlled, double-blind, cross-over study to evaluate the effect of ezetimibe 10 mg and simvastatin 40 mg, coadministered and alone, on the in vivo kinetics of apolipoprotein (apo) B-48 and B-100 in humans. Subjects underwent a primed-constant infusion of a stable isotope in the fed state. The coadministration of simvastatin and ezetimibe significantly reduced plasma concentrations of cholesterol (–43.0%), LDL-C (–53.6%), and triglycerides (–44.0%). Triglyceride-rich lipoproteins (TRL) apoB-48 pool size (PS) was significantly decreased (–48.9%) following combination therapy mainly through a significant reduction in TRL apoB-48 production rate (PR) (–38.0%). The fractional catabolic rate (FCR) of VLDL and LDL apoB-100 were significantly increased with all treatment modalities compared with placebo, leading to a significant reduction in the PS of these fractions. We also observed a positive correlation between changes in TRL apoB-48 PS and changes in TRL apoB-48 PR (r = 0.85; P < 0.0001) with combination therapy. Our results indicate that treatment with simvastatin plus ezetimibe is effective in reducing plasma TRL apoB-48 levels and that this effect is most likely mediated by a reduction in the intestinal secretion of TRL apoB-48. Our study also indicated that the reduction in LDL-C concentration following combination therapy is mainly driven by an increase in FCR of apoB-100 containing lipoproteins.

Supplementary key words Apolipoprotein B-48 • apolipoprotein B-100 • cholesterol absorption and synthesis • gas chromatography/mass spectrometry • intestine • kinetic • liver

Abbreviations: Apo, apolipoprotein; BMI, body mass index; CHD, coronary heart disease; FCR, fractional catabolic rate; HMG-CoA, 3-hydroxy-3-methylglutaryl CoA; LDL-C, low density lipoprotein cholesterol; MTP, microsomal triglyceride transfer protein; PR, production rate; PS, pool size; TRL, triglyceride-rich lipoproteins

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