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

• Ohishi Kenji

  Yakult Central Institute for Microbiological Research

• Sawada Haruji

  Yakult Central Institute for Microbiological Research

• Yoshida Yasuto

  Yakult Central Institute for Microbiological Research

• Hatano Hiroshi

  Yakult Central Institute for Microbiological Research

• Aiyama Ritsuo

  Yakult Central Institute for Microbiological Research

• Watanabe Tsunekazu

  Yakult Central Institute for Microbiological Research

• Yokokura Teruo

  Yakult Central Institute for Microbiological Research

書誌事項

タイトル別名

• 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

抄録

The metabolic stability of the acyl-CoA: cholesterol O-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 the 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.

収録刊行物

• Ｂｉｏｌｏｇｉｃａｌ　＆　Ｐｈａｒｍａｃｅｕｔｉｃａｌ　Ｂｕｌｌｅｔｉｎ

  Ｂｉｏｌｏｇｉｃａｌ　＆　Ｐｈａｒｍａｃｅｕｔｉｃａｌ　Ｂｕｌｌｅｔｉｎ 26 (5), 600-607, 2003

  公益社団法人 日本薬学会

キーワード

• YIC-708-424
• metabolic stability
• hypocholesterolemic activity
• acyl-CoA: cholesterol <i>O</i>-acyltransferase (ACAT) inhibitor
• apparent kinetic parameter
• Sprague-Dawley rat

詳細情報

• CRID: 1390001204625645696
• NII論文ID: 110003608482
• NII書誌ID: AA10885497
• DOI: 10.1248/bpb.26.600
• COI: 1:CAS:528:DC%2BD3sXltVejurc%3D
• ISSN: 13475215
• ISSN: 09186158
• NDL書誌ID: 6517080
• PubMed: 12736497
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I6517080
• Web Site: http://www.jstage.jst.go.jp/article/bpb/26/5/26_5_600/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2003297794
• 本文言語コード: en
• データソース種別:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
• 抄録ライセンスフラグ: 使用不可