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OtherCARDIOVASCULAR PHARMACOLOGY

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
Journal of Pharmacology and Experimental Therapeutics January 1998, 284 (1) 43-50;
Teruhisa Ichihashi
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Mariko Izawa
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Kenji Miyata
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Takuji Mizui
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Koichiro Hirano
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Yasushi Takagishi
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Abstract

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 andl-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.

Footnotes

  • Send reprint requests to: Dr. Teruhisa Ichihashi, Formulation R & D Laboratories, Shionogi & Co., Ltd., Fukushima-ku, Osaka 553, Japan.

  • Abbreviations:
    TCA
    taurocholic acid
    GCA
    glycocholic acid
    CA
    cholic acid
    VLDL
    very low-density lipoprotein
    LDL
    low-density lipoprotein
    HDL
    high-density lipoprotein
    HMG CoA
    3-hydroxy-3-methylglutaryl coenzyme A
    HEPES
    N-(2-hydroxyethyl)-piperazine-N′-2-ethanesulfonic acid
    TLC
    thin-layer chromatography
    • Received March 31, 1997.
    • Accepted September 15, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 1
1 Jan 1998
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OtherCARDIOVASCULAR PHARMACOLOGY

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
Journal of Pharmacology and Experimental Therapeutics January 1, 1998, 284 (1) 43-50;

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OtherCARDIOVASCULAR PHARMACOLOGY

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
Journal of Pharmacology and Experimental Therapeutics January 1, 1998, 284 (1) 43-50;
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