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.
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 x 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.
Ohishi
Kenji
K
Yakult Central Institute for Microbiological Research, Kunitachi, Tokyo, Japan. kenji-ooishi@yakult.co.jp
Sawada
Haruji
H
Yoshida
Yasuto
Y
Hatano
Hiroshi
H
Aiyama
Ritsuo
R
Watanabe
Tsunekazu
T
Yokokura
Teruo
T
D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000648:ultrastructure; D008099:Liver / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D010879:Piperazines / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013057:Spectrum Analysis
D004791:Enzyme Inhibitors; C482679:N-(4-benzyloxy-3, 5-dimethoxycinnamoyl)-N'-(2, 4-dimethylphenyl)piperazine; D010879:Piperazines