The Metabolic Stability of Acyl-CoA: Cholesterol O-Acyltransferase (ACAT) Inhibitors, N-(4-Benzyloxy-3,5-dimethoxycinnamoyl)-N'-(2,4- dimethylphenyl)piperazine (YIC-708-424) and Its Derivatives in Rat Liver and Intestinal Epithelium

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概要

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• The metabolic stability of the acyl-CoA: cholesterol 0-acyltransferase (ACAT) inhibitor N-(4-benzyloxy-3,5- dimethoxycinnamoyl)-N'-(2,4-dimethylphenyl)piperazine (YIC-708-424) and its n-alkoxy derivatives containing an alkyl chain of 3 or 7 to 10 carbons, which exhibited different hypocholesterolemic activities, was investigated in vivo and in vitro in rats. After the oral administration of YIC-708-424 to rats at a dose of 5 mg/kg/d for 7 d, the parent compound was not detected in the blood. On the other hand, when then n-alkoxy derivatives were administered to rats, an increase in the alkyl chain length produced a progressive increase in the blood concentration of the parent compound. Both in the blood of rats administered YIC-708-424 and in the reaction mixture after the incubation of YIC-708-424 with rat hepatic 9000×g supernatants, an inactive major metabolite, N-(4-benzyloxy-3,5-dimethoxycinnamoyl)-N'-(4-carboxyl-2-methylphenyl)piperazine, was observed. The ratio of the maximum velocity to the apparent Michaelis-Menten constant (V_<max>/K_M) for the degradation of the n-propyloxy derivative in rat hepatic and intestinal microsomes was almost equivalent to that of YIC-708-424. On the other hand, an increase in the alkyl chain length of n-alkoxy derivatives produced a progressive decrease in V_<max>/K_M for the degradation of these compounds. Additionally, the in vivo hypocholesterolemic activities of YIC-708-424 and its n-alkoxy derivatives were positively correlated with the blood concentration of the parent compound and were negatively correlated with their V_<max>/K_m. These results suggest that the metabolic stability of ACAT inhibitors in the liver and intestinal epithelium, which are the major target organs of these compounds, has a strong influence on their pharmacological activities in vivo.

• 公益社団法人日本薬学会の論文
• 2003-05-01

著者

• Yokokura T

  Yakult Central Inst. Microbiological Res. Tokyo Jpn

• Yokokura Teruo

  Yakult Central Institute For Microbiological Research

• Yokokura Teruo

  Yakult Institute For Microbiological Research

• Yokokura Teruo

  Yakult Cent. Inst. Miorobiol.

• Haga Hiroko

  Division Of Clinical Chemistry Niigata Cancer Center Hospital

• Yoshida Yuki

  Showa Pharmaceutical University

• SAWADA Haruji

  Yakult Central Institute for Microbiological Research

• Sawada H

  Yakult Central Inst. For Microbiological Res.

• Hatano H

  Yakult Central Institute For Microbiological Research

• Hatano Hiroshi

  Optics Technology Division Takatsuki Laboratory Minolta Co. Ltd.

• Yoshida Y

  Yakult Central Inst. For Microbiological Res.

• Sansawa H

  Yakult Inst. Microbiological Res. Tokyo Jpn

• Watanabe T

  Fukuyama Univ. Hiroshima Jpn

• OHISHI Kenji

  Yakult Central Institute for Microbiological Research

• YOSHIDA Yasuto

  Yakult Central Institute for Microbiological Research

• HATANO Hiroshi

  Yakult Central Institute for Microbiological Research

• WATANABE Tsunekazu

  Yakult Central Institute for Microbiological Research

• AIYAMA Ritsuo

  Yakult Central Institute for Microbiological Research

• Ohishi K

  Yakult Honsha European Research Center For Microbiology Esv

• Aiyama R

  Yakult Central Institute For Microbiological Research

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