Novel non-systemic inhibitor of ileal apical Na+-dependent bile acid transporter reduces serum cholesterol levels in hamsters and monkeys
article
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
Topics
Apical sodium-dependent bile acid transporterCholesterolEnterohepatic circulationHamsterHypocholesterolemic agentMonkeyCarbon 14CholesterolHigh density lipoprotein cholesterolIleum apical bile acid transporter inhibitorPhospholipidPiperidine derivativeR 146224Taurocholic acidTriacylglycerolTritiumUnclassified drugBile acidCarrier proteinCotransporterOrganic anion transporterQuinoline derivativeSodiumSodium bile acid cotransporterSodium-bile acid cotransporterAbsorptionAnimal experimentAnimal tissueBile duct fistulaBile flowCholesterol blood levelCholesterol esterificationConcentration responseControlled studyDietDose responseDrug mechanismEmbryoFeedingHuman cellHypercholesterolemiaHypolipemiaInhibition kineticsTimeTriacylglycerol blood levelUrinary excretionBiosynthesisBloodCell lineDrug antagonismDrug effectGeneticsIn vitro studyMacacaMetabolismPhysiologySprague Dawley ratSyrian hamsterAnimalsAnticholesteremic AgentsBile Acids and SaltsCell LineCholesterolCricetinaeHumansIleumMacaca fascicularisMaleMembrane Transport ProteinsMesocricetusOrganic Anion Transporters, Sodium-DependentPiperidinesQuinolinesRatsRats, Sprague-DawleySodiumSymportersTaurocholic Acid
TNO Identifier
239312
ISSN
00142999
Source
European Journal of Pharmacology, 539(1-2), pp. 89-98.
Pages
89-98
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