title: Novel non-systemic inhibitor of ileal apical Na+-dependent bile acid transporter reduces serum cholesterol levels in hamsters and monkeys.
abstract: 1-{7-[(1-(3,5-Diethoxyphenyl)-3-{[(3,5-difluorophenyl)(ethyl)amino]carbonyl}-4-oxo-1,4-dihydroquinolin-7-yl)oxy]heptyl}-1-methylpiperidinium bromide, R-146224, is a potent, specific ileum apical sodium-dependent bile acid transporter (ASBT) inhibitor; concentrations required for 50% inhibition of [3H]taurocholate uptake in human ASBT-expressing HEK-293 cells and hamster ileum tissues were 0.023 and 0.73 microM, respectively. In bile-fistula rats, biliary and urinary excretion 48 h after 10 mg/kg [14C]R-146224, were 1.49+/-1.75% and 0.14+/-0.05%, respectively, demonstrating extremely low absorption. In hamsters, R-146224 dose-dependently reduced gallbladder bile [3H]taurocholate uptake (ED50: 2.8 mg/kg). In basal diet-fed hamsters, 14-day 30-100 mg/kg R-146224 dose-dependently reduced serum total cholesterol (approximately 40%), high density lipoprotein (HDL) cholesterol (approximately 37%), non-HDL cholesterols (approximately 20%), and phospholipids (approximately 20%), without affecting serum triglycerides, associated with reduced free and esterified liver cholesterol contents. In normocholesterolemic cynomolgus monkeys, R-146224 specifically reduced non-HDL cholesterol. In human ileum specimens, R-146224 dose-dependently inhibited [3H]taurocholate uptake. Potent non-systemic ASBT inhibitor R-146224 decreases bile acid reabsorption by inhibiting the ileal bile acid active transport system, resulting in hypolipidemic activity.
authors: Pharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
authors: Ken
authors: K
authors: Kitayama
authors: Daisuke
authors: D
authors: Nakai
authors: Keita
authors: K
authors: Kono
authors: Arthur Gerritsen
authors: AG
authors: van der Hoop
authors: Hitoshi
authors: H
authors: Kurata
authors: Elly C
authors: EC
authors: de Wit
authors: Louis H
authors: LH
authors: Cohen
authors: Toshimori
authors: T
authors: Inaba
authors: Takafumi
authors: T
authors: Kohama