Author: Yoshitada Notsu ; Hiroyuki Hagihara ; Yoshikuni Ito ; Yuri Sakuma ; Akira Nagayoshi ; Kunio Nakahara ; Kazuhiko Ohne ; Seitaro Mutoh ; Masakuni Okuhara

Recent studies have shown that acyl-CoA:cholesterol acyltransferase (ACAT) plays an important role in the initiation of diabetes-associated hypercholesterolemia. To confirm this hypothesis, effects of a potent ACAT inhibitor, FR145237, on diet-induced hypercholesterolemia were examined in streptozotocin (STZ)-induced diabetic rats. One-week feeding of 1% cholesterol and 0.5% cholic acid to normal rats and STZ-induced diabetic rats increased plasma cholesterol levels in both groups, and the response was more remarkable in the STZ rats than in the normal ones (1266 +/- 476 mg/dl and 146 +/- 7 mg/dl, respectively). FR145237 dose-dependently reduced the rise in plasma cholesterol levels in the STZ rats and the levels were almost normalized by treatment with 1 mg/kg/day of the compound. These results suggest that hyperresponse to dietary cholesterol was induced in the STZ rats and that ACAT is involved in the hyperresponse. The effects of FR145237 on other plasma lipids such as high density lipoprotein (HDL) cholesterol and triglyceride (TG) levels were also examined.

01 Oct 1996·Toxicology and Applied PharmacologyQ3 · MEDICINE

Difference between Normal and WHHL Rabbits in Susceptibility to the Adrenal Toxicity of an Acyl-CoA:Cholesterol Acyltransferase Inhibitor, FR145237

Q3 · MEDICINE

Article

Author: Kyoichi Shimomura ; Jyunya Suzuki ; Kohki Iwanami ; Masahiko Matsuo ; Masaaki Tomoi ; Masaharu Hashimoto

The adrenal toxicity of an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, FR145237, was investigated using Japanese White (normal) and low density lipoprotein (LDL) receptor deficient Watanabe heritable hyperlipidemic (WHHL) rabbits. In the normal rabbits, severe necrosis of the cells in the zona fasciculata and reticularis was observed 24 hr after intravenous injection of 3.2 mg/kg of FR145237, whereas no morphological changes could be found in the adrenal cells of the WHHL rabbits in spite of a higher plasma concentration of the drug. Since most of the FR145237 (87%) in the plasma of the WHHL rabbits was recovered in the LDL fraction 1 hr after intravenous injection of the drug (3.2 mg/kg), it was hypothesized that the delivery of the drug to the adrenal cells may be limited by the LDL receptor deficiency. However, the concentration of FR145237 in the adrenal gland of the WHHL rabbits (13.3 microg/g) was identical to that in the normal rabbits (13.6 microg/g). These results suggest that the susceptibility of the adrenal cells of the WHHL rabbits to the toxicity of FR145237 truly differs from that of normal rabbits, and that the WHHL rabbit may be a useful animal model for the investigation of the mechanisms of the adrenal toxicity of ACAT inhibitors.

01 Dec 1995·Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism

Effect of FR145237, a novel ACAT inhibitor, on atherogenesis in cholesterol-fed and WHHL rabbits. Evidence for a direct effect on the arterial wall

Article

Author: Kyoichi Shimomura ; Futoshi Ito ; Miho Aketa ; Masahiko Matsuo ; Akiko Konto ; Masaaki Tomoi

The hypocholesterolemic and antiatherosclerotic activities of FR145237, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, were evaluated in cholesterol-fed and Watanabe heritable hyperlipidemic (WHHL) rabbits. In the first experiment, rabbits were fed a high cholesterol (1% cholesterol) diet for 2 weeks and further fed a high cholesterol diet containing FR145237 for 8 weeks. FR145237 (0.1, 0.32 and 1.0 mg/kg) dose-dependently lowered the plasma total cholestrol levels by 80%, 96% and 97%, respectively. and reduced aortic atherosclerosis by 44%, 90% and 90%, respectively. To clarify a direct effect of FR145237 at the aortic wall, a second experiment was performed. Rabbits were fed a high-cholesterol diet for 8 weeks to establish aortic atherosclerosis and then fed a normal diet with or without FR145237 for 8 weeks. Cholesterol content in the aorta and the liver was significantly reduced in the FR145237 group (10 mg/kg) by 50% and 43%, respectively, though plasma total cholesterol level did not differ from that in the control group. In the WHHL rabbits, FR145237 (10 mg/kg) did not affect plasma cholesterol level but significantly reduced the atherosclerotic lesion in the coronary arteries by 61%. These results suggest that FR145237 potently lowers the plasma cholesterol level in hypercholesterolemia induced by dietary cholesterol but not that by LDL receptor deficiency, and that FR145237 has a direct antiatherosclerotic activity on the arterial wall independent of its hypocholesterolemic activity.

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Indication	Highest Phase	Country/Location	Organization	Date
Hyperlipidemias	Discovery	JP	Fujisawa Pharmaceutical Co., Ltd.	-

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