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Novel non-systemic inhibitor of ileal apical Na+-dependent bile acid transporter reduces serum cholesterol levels in hamsters and monkeys

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Author: Kitayama, K. · Nakai, D. · Kono, K. · Hoop, A.G. van der · Kurata, H. · Wit, E.C. de · Cohen, L.H. · Inaba, T. · Kohama, T.
Type:article
Date:2006
Institution: TNO Preventie en Gezondheid
Source:European Journal of Pharmacology, 1-2, 539, 89-98
Identifier: 239312
doi: doi:10.1016/j.ejphar.2006.04.005
Keywords: Biology · Apical sodium-dependent bile acid transporter · Cholesterol · Enterohepatic circulation · Hamster · Hypocholesterolemic agent · Monkey · Carbon 14 · Cholesterol · High density lipoprotein cholesterol · Ileum apical bile acid transporter inhibitor · Phospholipid · Piperidine derivative · R 146224 · Taurocholic acid · Triacylglycerol · Tritium · Unclassified drug · Bile acid · Carrier protein · Cotransporter · Organic anion transporter · Quinoline derivative · Sodium · Sodium bile acid cotransporter · Sodium-bile acid cotransporter · Absorption · Animal experiment · Animal tissue · Bile duct fistula · Bile flow · Cholesterol blood level · Cholesterol esterification · Concentration response · Controlled study · Diet · Dose response · Drug mechanism · Embryo · Feeding · Human cell · Hypercholesterolemia · Hypolipemia · Inhibition kinetics · Time · Triacylglycerol blood level · Urinary excretion · Biosynthesis · Blood · Cell line · Drug antagonism · Drug effect · Genetics · In vitro study · Macaca · Metabolism · Physiology · Sprague Dawley rat · Syrian hamster · Animals · Anticholesteremic Agents · Bile Acids and Salts · Cell Line · Cholesterol · Cricetinae · Humans · Ileum · Macaca fascicularis · Male · Membrane Transport Proteins · Mesocricetus · Organic Anion Transporters, Sodium-Dependent · Piperidines · Quinolines · Rats · Rats, Sprague-Dawley · Sodium · Symporters · Taurocholic Acid

Abstract

1-{7-[(1-(3,5-Diethoxyphenyl)-3-{[(3,5-difluorophenyl)(ethyl)amino]carbo nyl}-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 μM, 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 (∼ 40%), high density lipoprotein (HDL) cholesterol (∼ 37%), non-HDL cholesterols (∼ 20%), and phospholipids (∼ 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. © 2006 Elsevier B.V. All rights reserved. Chemicals / CAS: carbon 14, 14762-75-5; cholesterol, 57-88-5; taurocholic acid, 145-42-6, 59005-70-8, 81-24-3; tritium, 10028-17-8; carrier protein, 80700-39-6; sodium, 7440-23-5; 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; Anticholesteremic Agents; Bile Acids and Salts; Cholesterol, 57-88-5; Membrane Transport Proteins; Organic Anion Transporters, Sodium-Dependent; Piperidines; Quinolines; Sodium, 7440-23-5; sodium-bile acid cotransporter, 145420-23-1; Symporters; Taurocholic Acid, 81-24-3