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OtherCARDIOVASCULAR PHARMACOLOGY

In Vivo Metabolism-Based Discovery of a Potent Cholesterol Absorption Inhibitor, SCH58235, in the Rat and Rhesus Monkey through the Identification of the Active Metabolites of SCH48461

Margaret Van Heek, Constance F. France, Douglas S. Compton, Robbie L. Mcleod, Nathan P. Yumibe, Kevin B. Alton, Edmund J. Sybertz and Harry R. Davis Jr.
Journal of Pharmacology and Experimental Therapeutics October 1997, 283 (1) 157-163;
Margaret Van Heek
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Constance F. France
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Douglas S. Compton
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Robbie L. Mcleod
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Nathan P. Yumibe
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Kevin B. Alton
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Edmund J. Sybertz
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Harry R. Davis Jr.
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Abstract

SCH48461 is a selective and highly potent inhibitor of cholesterol absorption. In rats, SCH48461 is rapidly and completely metabolized in the first pass through the body. To compare the activity of the metabolites of SCH48461 with SCH48461 itself, an intestinally cannulated, bile duct-cannulated rat model for cholesterol absorption was developed. SCH48461 inhibited the absorption of cholesterol by 70%, whereas bile containing the metabolites of SCH48461 (henceforth, “metabolite bile”) inhibited the absorption by greater than 95%. Very little of the recovered radioactive dose of SCH48461 was located in the intestinal lumen (7%) or wall (4%), whereas 85% appeared in bile. However, in rats treated with metabolite bile, 62% of the dose remained in the lumen, 13% was associated with the wall and only 24% reappeared in bile, which suggests that the activity of the metabolite bile may be related to its higher retention in the intestinal wall. Rats treated with metabolite bile had 64% and 84% less drug-related radioactivity in their plasma and livers, respectively, compared with animals treated with SCH48461, which indicates that the metabolites are systemically less available than SCH48461. The metabolites in bile were separated by high-performance liquid chromatography; the most active fraction in the bile duct-cannulated rat model was identified by mass spectrometry as the glucuronide of the C4-phenol of SCH48461. The other fractions had moderate or no activity. Through the identification of the most active biliary metabolites of SCH48461 in the rat, we have discovered SCH58235, a novel cholesterol absorption inhibitor which is 400 times more potent than SCH48461 in the cholesterol-fed rhesus monkey.

Footnotes

  • Send reprint requests to: Margaret Van Heek, K15–2-2600, Schering-Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033.

  • Abbreviations:
    SAR
    structure-activity relationship
    ACAT
    acyl-CoA:cholesterol acyltransferase
    RP-HPLC
    reverse phase-high pressure liquid chromatography
    TLC
    thin layer chromatography
    LDL
    low density lipoprotein
    LC
    liquid chromatography
    MS
    mass spectrometry
    HMG-CoA
    hydroxymethylglutaryl coenzyme A
    • Received February 13, 1997.
    • Accepted June 30, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 283, Issue 1
1 Oct 1997
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OtherCARDIOVASCULAR PHARMACOLOGY

In Vivo Metabolism-Based Discovery of a Potent Cholesterol Absorption Inhibitor, SCH58235, in the Rat and Rhesus Monkey through the Identification of the Active Metabolites of SCH48461

Margaret Van Heek, Constance F. France, Douglas S. Compton, Robbie L. Mcleod, Nathan P. Yumibe, Kevin B. Alton, Edmund J. Sybertz and Harry R. Davis
Journal of Pharmacology and Experimental Therapeutics October 1, 1997, 283 (1) 157-163;

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OtherCARDIOVASCULAR PHARMACOLOGY

In Vivo Metabolism-Based Discovery of a Potent Cholesterol Absorption Inhibitor, SCH58235, in the Rat and Rhesus Monkey through the Identification of the Active Metabolites of SCH48461

Margaret Van Heek, Constance F. France, Douglas S. Compton, Robbie L. Mcleod, Nathan P. Yumibe, Kevin B. Alton, Edmund J. Sybertz and Harry R. Davis
Journal of Pharmacology and Experimental Therapeutics October 1, 1997, 283 (1) 157-163;
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