Antidyslipidemic effects of a farnesoid X receptor antagonist in primates.
OBJECTIVE
We investigated antidyslipidemic effects of a farnesoid X receptor antagonist compound-T3 in non-human primates as a novel treatment approach for dyslipidemia.


METHODS
Cynomolgus monkeys were fed a high-fat diet over 3 weeks. Drugs were administered to the monkeys for a week, and their plasma and fecal lipid parameters were measured.


RESULTS
Compound-T3 dose-dependently decreased the plasma non-high-density lipoprotein (non-HDL) cholesterol and apolipoprotein B levels in high-fat diet-fed cynomolgus monkeys. The plasma levels of 7α-hydroxy-4-cholesten-3-one, a marker of hepatic cholesterol 7α-hydroxylase activity, and total fecal bile acid levels increased, suggesting that the hypocholesterolemic effects would be dependent on the activation of cholesterol catabolism in the liver. Compound-T3 significantly increased the plasma levels of HDL cholesterol and apolipoprotein A-I. In this condition, the cholesterol absorption inhibitor ezetimibe significantly decreased the plasma non-HDL cholesterol levels and increased the fecal cholesterol levels without affecting plasma HDL cholesterol and triglyceride levels. Bile acid sequestrant cholestyramine tended to decrease plasma non-HDL cholesterol and increase fecal bile acid levels. The cholesteryl ester transfer protein inhibitor torcetrapib significantly increased plasma HDL cholesterol levels without affecting plasma non-HDL cholesterol and fecal cholesterol levels.


CONCLUSIONS
The results of ezetimibe, cholestyramine, and torcetrapib treatments indicate that our high-fat diet fed monkey model would be a preferred animal model for studying non-statin type antidyslipidemic drugs. Compound-T3 significantly decreased non-HDL cholesterol levels and increased HDL cholesterol levels in the monkey model, suggesting that a farnesoid X receptor antagonist could be a therapeutic option in human dyslipidemia.
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: yuichiro.amano@takeda.com.
Yuichiro
Y
Amano
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Mitsuyuki
M
Shimada
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Shotaro
S
Miura
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Ryutaro
R
Adachi
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Ryuichi
R
Tozawa
D000818:Animals; D000924:Anticholesteremic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D050171:Dyslipidemias / Q000097:blood* / Q000188:drug therapy*; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D011323:Primates; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome; D000099150:Receptor, Farnesoid X-Activated
D000924:Anticholesteremic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated
Cholestyramine; Ezetimibe; Farnesoid X receptor antagonist; HDL cholesterol; LDL cholesterol; Torcetrapib