Combinational effects of farnesoid X receptor antagonist and statin on plasma lipid levels and low-density lipoprotein clearance in guinea pigs

• Published in: Life sciences (1973) Vol. 108; no. 1; pp. 7 - 12
• Main Authors: Amano, Yuichiro, Ishikawa, Eiichiro, Shinozawa, Emiko, Shimada, Mitsuyuki, Miura, Shotaro, Adachi, Ryutaro, Tozawa, Ryuichi
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 11.07.2014
• Subjects: Animals; Anticholesteremic Agents - administration & dosage; Anticholesteremic Agents - pharmacology; Atorvastatin; Atorvastatin Calcium; Benzoates - administration & dosage; Benzoates - pharmacology; Cholestenones - blood; Cholesterol - blood; Cholesterol, LDL - blood; Combination therapy; Compound-T8; Dose-Response Relationship, Drug; Drug Therapy, Combination; Dyslipidemia; Farnesoid X receptor antagonist; Guinea pig; Guinea Pigs; Heptanoic Acids - administration & dosage; Heptanoic Acids - pharmacology; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Lipoproteins, HDL - blood; Male; Pyrazoles - administration & dosage; Pyrazoles - pharmacology; Pyrroles - administration & dosage; Pyrroles - pharmacology; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Time Factors; Atorvastatin; Farnesoid X receptor antagonist; Guinea pig; Combination therapy; Compound-T8; Dyslipidemia
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2014.04.029

We previously reported anti-dyslipidemic effects of a farnesoid X receptor antagonist in monkeys. In this study, we compared the cholesterol-lowering effects of single and combined administration of a farnesoid X receptor antagonist, compound-T8, and the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor atorvastatin in a guinea pig model. Plasma levels of 7α-hydroxy-4-cholesten-3-one, a marker of hepatic cholesterol 7α-hydroxylase activity, were measured after a single administration of compound-T8. The effects of compound-T8 or atorvastatin on plasma cholesterol levels and low-density lipoprotein (LDL) clearance were investigated after 14 or 16days of repeated dosing, respectively. Fractional catabolic rate of plasma LDL was estimated by intravenous injection of DiI-labeled human LDL. The cholesterol-lowering effects of combination therapy were investigated after 7days of repeated treatment. Compound-T8 (10 and 30mg/kg) increased plasma 7α-hydroxy-4-cholesten-3-one levels in a dose-dependent manner. Single administration of compound-T8 (30mg/kg) and atorvastatin (30mg/kg) reduced plasma non-high-density lipoprotein (non-HDL) cholesterol levels by 48% and 46%, respectively, and increased clearance of plasma DiI-labeled LDL by 29% and 35%, respectively. Compound-T8 (10mg/kg) or atorvastatin (10mg/kg) reduced non-HDL cholesterol levels by 19% and 25%, respectively, and combination therapy showed an additive effect and lowered cholesterol levels by 48%. Similar to atorvastatin, compound-T8 reduced plasma non-HDL cholesterol levels accompanied with accelerated LDL clearance in guinea pigs. Combination therapy additively decreased plasma non-HDL cholesterol levels. Therefore, monotherapy with a farnesoid X receptor antagonist and combination therapy of a farnesoid X receptor antagonist with atorvastatin would be attractive dyslipidemia treatment options.