Vol. 284, Issue 1, 43-50, 1998

Mechanism of Hypocholesterolemic Action of S-8921 in Rats: S-8921 Inhibits Ileal Bile Acid Absorption

Teruhisa Ichihashi, Mariko Izawa, Kenji Miyata, Takuji Mizui, Koichiro Hirano and Yasushi Takagishi

Formulation R & D Laboratories (T.I., M.I, K.H., Y.T.) and Discovery Research Laboratories II (K.M., T.M.), Shionogi & Co., Ltd., Fukushima-ku, Osaka 553, Japan

The mechanism of the hypocholesterolemic action of S-8921, methyl 1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy- 6,7,8-trimethoxy-2-naphthoate, was examined in rats. In diet-induced hypercholesterolemic rats, 2 weeks oral administration of S-8921 dose- and time-dependently decreased plasma cholesterol level in the daily dose range of 0.1to10 mg/kg. Results with the dual-isotope plasma ratio method indicated that S-8921 inhibits cholesterol absorption from the intestine and enhances its elimination from the body. The in situ loop method showed that S-8921 does not inhibit the absorption of cholesterol from rat jejunum, clearly inhibits active absorption of taurocholic acid (TCA) and glycocholic acid (GCA) from rat ileum and does not inhibit passive absorption of cholic acid (CA) from the rat jejunum. In rat ileal brush-border membrane vesicles, S-8921 inhibited the sodium-dependent uptake of TCA in a concentration-dependent manner with IC₅₀ of 2.1 µM, not the Na⁺-dependent D-glucose and L-alanine uptake. These results suggest that S-8921 is a potent, selective inhibitor of the Na⁺-dependent bile acid transport system in the ileal mucosal cell brush-border membrane, and this inhibition is the mechanism by which this drug decreases intestinal bile acid reabsorption to result in a significant decrease of plasma cholesterol.