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

Intestinal cholesterol esterification by the enzyme acyl‐CoA:cholesterol acyltransferase (ACAT) is a presumed 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‐lH‐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. Clinical Pharmacology and Therapeutics (1994) 56, 65–74; doi: