| Effect of dalcetrapib, a CETP modulator, on non-cholesterol sterol markers of cholesterol homeostasis in healthy subjects. | |
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MedLine Citation:
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PMID: 21982411 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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OBJECTIVE: Subjects with high HDL-C show elevated plasma markers of cholesterol absorption and reduced markers of cholesterol synthesis. We evaluated the effect of dalcetrapib, a cholesteryl ester transfer protein modulator, on markers of cholesterol homeostasis in healthy subjects. METHODS: Dalcetrapib was administered daily with or without ezetimibe in a randomized, open-label, crossover study in 22 healthy subjects over three 7-day periods: dalcetrapib 900mg, ezetimibe 10mg, dalcetrapib 900mg plus ezetimibe 10mg. Plasma non-cholesterol sterols lathosterol and desmosterol (cholesterol synthesis markers) and campesterol, β-sitosterol and cholestanol (intestinal cholesterol absorption markers) were measured. A hamster model was used to compare the effect of dalcetrapib and torcetrapib with or without ezetimibe on these markers and determine the effect of dalcetrapib on cholesterol absorption. RESULTS: Dalcetrapib increased campesterol, β-sitosterol, and cholestanol by 27% (p=0.001), 32% (p<0.001), and 12% (p=0.03), respectively, in man (non-cholesterol sterol/cholesterol ratio). Dalcetrapib+ezetimibe reduced campesterol by 11% (p=0.02); β-sitosterol and cholestanol were unaffected. Lathosterol and desmosterol were unchanged with dalcetrapib, but both increased with ezetimibe alone (56-148%, p<0.001) and with dalcetrapib+ezetimibe (32-38%, p<0.001). In hamsters, dalcetrapib and torcetrapib increased HDL-C by 49% (p=0.04) and 72% (p=0.003), respectively. Unlike torcetrapib, dalcetrapib altered cholesterol homeostasis towards increased markers of cholesterol absorption; cholesterol synthesis markers were unaffected by either treatment. Dalcetrapib did not change plasma (3)H-cholesterol level but increased (3)H-cholesterol in plasma HDL vs non-HDL, after oral dosing of labeled cholesterol. CONCLUSION: Dalcetrapib specifically increased markers of cholesterol absorption, most likely reflecting nascent HDL lipidation by intestinal ABCA1, without affecting markers of synthesis. |
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Authors:
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Eric J Niesor; Evelyne Chaput; Andreas Staempfli; Denise Blum; Michael Derks; David Kallend |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-9-16 |
Journal Detail:
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Title: Atherosclerosis Volume: - ISSN: 1879-1484 ISO Abbreviation: - Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-10-10 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0242543 Medline TA: Atherosclerosis Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011 Elsevier Ireland Ltd. All rights reserved. |
Affiliation:
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Discovery Research Metabolic Disease, F. Hoffmann-La Roche Ltd, Basel, Switzerland. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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