Effect of the acyl-CoA:cholesterol acyltransferase inhibitor DuP 128 on cholesterol absorption and serum cholesterol in humans

James W. Hainer, J. Greg Terry, Jill M. Connell, Hanna Zyruk, Rhonda M. Jenkins, Donna L. Shand, Peter J. Gillies, Kenneth J. Livak, Thomas L. Hunt, John R. Crouse

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61 Scopus citations

Abstract

Intestinal cholesterol esterification by the enzyme acyl-CoA:cholesterol acyltransferase (ACAT) is a pre- sumed prerequisite for cholesterol absorption. We evaluated the effect of a potent, poorly absorbed ACAT inhibitor (DuP 128: N'-(2,4-difluorophenyl)-N-[5-(4,5-diphenyl-1H-imidazol-2- ylthio)pentyl]-N-heptylurea) on cholesterol absorption in a randomized trial. Thirty subjects received DuP 128 for 7 weeks, 10 each at 900 mg per day, 1800 mg per day, and 3600 mg per day; six subjects received placebo; and nine subjects received 1 gm neomycin twice a day. Cholesterol absorption determinations used a continuous dual isotope 14C-cholesterol and 3H-beta sitosterol method. DuP 128 (pooled doses) induced at 14.4% ± 11.4% reduction in cholesterol absorption (p < 0.05 versus placebo): 17.6% ± 8.4% at 900 mg, 9.1% ± 11.4% at 1800 mg, and 17.1% ± 12.9% at 3600 mg. Neomycin induced a 26.4% ± 10.7% reduction (p < 0.01). After 6 weeks, neomycin reduced serum total and low-density lipoprotein cholesterol by 22.4% ± 9.2% and 24.0% ± 11.6%, respectively (p < 0.01 versus placebo). DuP 128 induced reductions of 3.9% ± 11% (difference not significant) and 4.95% ± 14.3% (p = 0.05). ACAT inhibitors limit cholesterol absorption in humans; however, the magnitude of the effect, as exemplified by DuP 128, is small.

Original languageEnglish (US)
Pages (from-to)65-74
Number of pages10
JournalClinical pharmacology and therapeutics
Volume56
Issue number1
StatePublished - Jul 1994
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

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