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Lack of Effect of Cholesterol Esterase Inhibitor CVT-1 on Cholesterol Absorption and LDL cholesterol in Humans

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Abstract

Two clinical trials were performed to test the hypothesis that CVT-1, a potent inhibitor of pancreatic cholesterol esterase, reduces percent cholesterol absorption and LDL cholesterol in humans. Measurements of cholesterol absorption were made with deuterated cholesterol tracers given orally and intravenously and detected in plasma by a new technique using negative ion mass spectrometry. Study 1 was a randomized, double-blind parallel study of CVT-1 treatment of doses of 0, 300, 1500, and 3000 mg/day in 19 subjects. Percent cholesterol absorption measured at baseline and again after 2 and 6 weeks showed no treatment effect and LDL cholesterol was unchanged. Study II was a randomized open-label crossover comparison between CVT-1 given as 1000 mg three times daily for 2 weeks and 187.5 mg hourly 16 hours/day for 2 weeks. Percent cholesterol absorption and plasma LDL cholesterol were not different between periods. We conclude that cholesterol esterase is not required for unesterified cholesterol absorption in human subjects.

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References

  1. Vahouny GV, Treadwell CR. Absolute requirement for free sterol for absorption by rat intestinal mucosa. Proc Soc Exp Biol Med 1964;116:496–498.

    Google Scholar 

  2. Borja CR, Vahouny GV, Treadwell CR. Role of bile and pancreatic juice in cholesterol absorption and esterification. Am J Physiol 1964;206:223–228.

    Google Scholar 

  3. Gallo LL, Clark SB, Myers S, Vahouny GV. Cholesterol absorption in rat intestine: Role of cholesterol esterase and acyl coenzyme A:cholesterol acyltransferase. J Lipid Res 1984;25:604–612.

    Google Scholar 

  4. Lopez-Candales A, Bosner MS, Spilburg CA, Lange LG. Cholesterol transport function of pancreatic cholesterol esterase: Directed sterol uptake and esterification in enterocytes. Biochemistry 1993;32:12085–12089.

    Google Scholar 

  5. Bosner MS, Gulick T, Riley DJS, Spilburg CA, Lange LG III. Receptor-like function of heparin in the binding and uptake of neutral lipids. Proc Nat Acad Sci 1988;85:7438–7442.

    Google Scholar 

  6. Bhat SG, Brockman HL. The role of cholesteryl ester hydrolysis and synthesis in cholesterol transport across rat intestinal mucosal membrane. A new concept. Biochem Biophys Res Comm 1982;109:486–492.

    Google Scholar 

  7. Watt SM, Simmonds WJ. The effect of pancreatic diversion on lymphatic absorption and esterification of cholesterol in the rat. J Lipid Res 1981;22:157–165.

    Google Scholar 

  8. Huang Y, Hui DY. Metabolic fate of pancreas-derived cholesterol esterase in intestine: An in vitro study using Caco-2 cells. J Lipid Res 1990;31:2029–2037.

    Google Scholar 

  9. Shamir R, Johnson WJ, Zolfaghari R, Lee HS, Fisher EA. Role of bile salt-dependent cholesteryl ester hydrolase in the uptake of micellar cholesterol by intestinal cells. Biochemistry 1995;34:6351–6358.

    Google Scholar 

  10. Spilburg C, Cox DG, Wang X Bernat BA, Bosner MS, Lange LG III. Identification of a species specific regulatory site in human pancreatic cholesterol esterase. Biochemistry 1995;34:15532–15538.

    Google Scholar 

  11. Zilversmit DB, Hughes LB. Validation of a dual-isotope plasma ratio method for measurement of cholesterol absorption in rats. J Lipid Res 1974;15:465–473.

    Google Scholar 

  12. Samuel P, McNamara DJ, Ahrens EH Jr., Crouse JR, Parker T. Further validation of the plasma isotope ratio method for measurement of cholesterol absorption. J Lipid Res 1982;23:480–489.

    Google Scholar 

  13. Bosner MS, Ostlund RE Jr, Osofisan O, Grosklos J, Fritschle C, Lange LG Assessment of percent cholesterol absorption in humans with stable isotopes. J Lipid Res 1993;34:1047–1053.

    Google Scholar 

  14. Ostlund RE Jr, Hsu F-F, Bosner MS, Stenson WF, Hachey DL. Quantification of cholesterol tracers by gas chromatography/negative ion chemical ionization mass spectrometry. J Mass Spectrometry 1996;31:1291–1296.

    Google Scholar 

  15. Bosner MS, Lange LG, Stenson WF, Ostlund RE Jr. Percent cholesterol absorption in normal women and men quantified with dual stable isotopic tracers and negative ion mass spectrometry. J Lipid Res 1999;40:302–308.

    Google Scholar 

  16. Manual of Laboratory Operations. Lipid Research Clinics Program. DHEW Publication no. NIH 75–628. 1974. United States Government Printing Office, Washington, D.C.

  17. Goodman DS, Noble RP. Turnover of plasma cholesterol in man. J Clin Invest 1968;47:231–241.

    Google Scholar 

  18. Howles PN, Carter CP, Hui, DY. Dietary free and esterified cholesterol absorption in cholesterol esterase (bile salt-stimulated lipase) gene-targeted mice. J Biol Chem 1996;271:7196–7202.

    Google Scholar 

  19. Field FJ, Mathur SN. β-Sitosterol: Esterification by intestinal acycoenzyme A:cholesterol acyltransferase (ACAT) and its effect on cholesterol esterification. J Lipid Res 1983;24:409–417.

    Google Scholar 

  20. Suckling KE, Stange EF. Role of acyl-coA:cholesterol acyltransferase in cellular cholesterol metabolism. J Lipid Res 1985;26:647–671.

    Google Scholar 

  21. Harris WS, Dujovne CA, von Bergmann K, Neal J, Akester J, Windsor SL, Greene D, Look Z. Effects of the ACAT inhibitor CL 277,082 on cholesterol metabolism in humans. Clin Pharmacol Ther 1990;48:189–194.

    Google Scholar 

  22. Thurnhofer H, Hauser H. Uptake of cholesterol by small intestinal brush border membrane is protein-mediated. Biochemistry 1990;29:2142–2148.

    Google Scholar 

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Authors and Affiliations

  1. Divisions of Cardiology, Department of Medicine, Washington University School of Medicine, Washington University School of Medicine, St. Louis, MO

    Matthew S. Bosner

  2. CV Therapeutics, Inc., 3172 Porter Drive, Palo Alto, CA

    Andrew A. Wolff

  3. Divisions of Endocrinology, Diabetes and Metabolism, Department of Medicine, Washington University School of Medicine, St. Louis, MO

    Richard E. Ostlund Jr.

Authors
  1. Matthew S. Bosner
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  2. Andrew A. Wolff
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  3. Richard E. Ostlund Jr.
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Bosner, M.S., Wolff, A.A. & Ostlund, R.E. Lack of Effect of Cholesterol Esterase Inhibitor CVT-1 on Cholesterol Absorption and LDL cholesterol in Humans. Cardiovasc Drugs Ther 13, 449–454 (1999). https://doi.org/10.1023/A:1007864208932

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  • DOI: https://doi.org/10.1023/A:1007864208932

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