抄録
The effect of KCD-232, a new hypolipidemic compound with a structure of 4-(4'-cholorobenzyloxy) benzyl nicotinate, on cholesterol absorption was studied by an isotope ratio method (IRM) in rats fed a normal diet and a high cholesterol diet (HCD). To validate this method, we also compared cholesterol absorption by a fecal radioactive method (FRM) with that simultaneously mesured by IRM. KCD-232 was orally administered once daily for 15 days. The following results were obtained.
1) Ratios of cholesterol absorption by IRM were almost constant values (range: 52-57, 58-61%) from 24h to 96h after isotope dosage in rats.
2) There was good to excellent agreement (r=0.9495, p<0.001) in cholesterol absorption indicated by IRM and FRM in the same rats.
3) KCD-232 inhibited both cholesterol absorption and serum cholesterol level in a dosedependent manner (37.5-300mg/kg/day) in normal rats and significantly reduced the former at dosage levels over 70mg/kg/day and the latter at over 37.5mg/kg/day, respectively. High positive correlations were also found between the administered dose of KCD-232 and the inhibition percent of cholesterol absorption (r=0.9982, p<0.001) and between the administered dose of KCD-232 and the inhibitory percent of serum cholesterol level (r=0.9750, p<0.001).
By contrast, colestipol (300mg/kg/day) used as a reference also inhibited cholesterol absorption but did not decrease serum cholesterol level at all.
4) Hypercholesterolemic rats fed a HCD have a slightly lower cholesterol absorption ratio and significantly decreased radioactivity of [3H] cholesterol intravenously administered in plasma compared with normocholesterolemic rats fed a normal diet.
KCD-232 (300mg/kg/day) significantly inhibited the elevation of serum total cholesterol (TCH) and TCH-(HDL-CH) levels by 86.4% and 89.3%, respectively, but increased the HDL-CH level by 24.7% (p<0.001), and consequently significantly improved the “Atherogenic index” indicated by the [TCH-(HDL-CH)]/HDL-CH ratio in rats fed a HCD.
KCD-232 significantly decreased further the lower cholesterol absorption by 22.5% (p<0.05) and stimulated the ratio of disappearance of [3H] cholesterol intravenously administered from the blood stream by 42.9% (p<0.001) in rats fed a HCD.
From these results, it can be assumed that the hypocholesterolemic activities of KCD-232 are in some part due to the inhibitory effect of cholesterol absorption from the intestine and in addition, might be due to the stimulated excretion of cholesterol from the blood stream in hypercholesterolemic rats.
