title: Effect of dalcetrapib, a CETP modulator, on non-cholesterol sterol markers of cholesterol homeostasis in healthy subjects.
abstract: 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 900 mg, ezetimibe 10mg, dalcetrapib 900 mg 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.
  
  
  CONCLUSIONS
  Dalcetrapib specifically increased markers of cholesterol absorption, most likely reflecting nascent HDL lipidation by intestinal ABCA1, without affecting markers of synthesis.
authors: Discovery Research Metabolic Disease, F. Hoffmann-La Roche Ltd, Basel, Switzerland. eric_j.niesor@roche.com
authors: Eric J
authors: EJ
authors: Niesor
authors: Evelyne
authors: E
authors: Chaput
authors: Andreas
authors: A
authors: Staempfli
authors: Denise
authors: D
authors: Blum
authors: Michael
authors: M
authors: Derks
authors: David
authors: D
authors: Kallend
mesh_terms: D000577:Amides; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001384:Azetidines / Q000494:pharmacology; D015415:Biomarkers / Q000097:blood; D004083:Cholestanol / Q000097:blood; D002784:Cholesterol / Q000031:analogs & derivatives / Q000097:blood*; D053480:Cholesterol Ester Transfer Proteins / Q000097:blood / Q000187:drug effects*; D008076:Cholesterol, HDL / Q000097:blood; D006224:Cricetinae; D018592:Cross-Over Studies; D003897:Desmosterol / Q000097:blood; D004952:Esters; D000069438:Ezetimibe; D006706:Homeostasis; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D008647:Mesocricetus; D023421:Models, Animal; D010840:Phytosterols / Q000097:blood; D011804:Quinolines / Q000494:pharmacology; D012855:Sitosterols / Q000097:blood; D013438:Sulfhydryl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D013557:Switzerland
chemical_list: D000577:Amides; D000924:Anticholesteremic Agents; D001384:Azetidines; D015415:Biomarkers; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D004952:Esters; D010840:Phytosterols; D011804:Quinolines; D012855:Sitosterols; D013438:Sulfhydryl Compounds; D003897:Desmosterol; C411602:dalcetrapib; C483909:torcetrapib; C021273:campesterol; C025473:gamma-sitosterol; C001521:lathosterol; D004083:Cholestanol; D002784:Cholesterol; D000069438:Ezetimibe