title: Combinational effects of farnesoid X receptor antagonist and statin on plasma lipid levels and low-density lipoprotein clearance in guinea pigs.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 16 days 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 7 days of repeated treatment.
  
  
  RESULTS
  Compound-T8 (10 and 30 mg/kg) increased plasma 7α-hydroxy-4-cholesten-3-one levels in a dose-dependent manner. Single administration of compound-T8 (30 mg/kg) and atorvastatin (30 mg/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%.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: yuichiro.amano@takeda.com.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Amano
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Ishikawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Shinozawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Mitsuyuki
authors.initials: M
authors.lastname: Shimada
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Miura
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Adachi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Tozawa
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000069059:Atorvastatin; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology*; D002783:Cholestenones / Q000097:blood; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006168:Guinea Pigs; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D008075:Lipoproteins, HDL / Q000097:blood; D008297:Male; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D013997:Time Factors; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000924:Anticholesteremic Agents; D000069059:Atorvastatin; D001565:Benzoates; D002783:Cholestenones; D002784:Cholesterol; D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008075:Lipoproteins, HDL; D011720:Pyrazoles; D011758:Pyrroles; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C002656:7 alpha-hydroxy-4-cholesten-3-one
keywords: Atorvastatin; Combination therapy; Compound-T8; Dyslipidemia; Farnesoid X receptor antagonist; Guinea pig