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Vol. 283, Issue 1, 157-163, 1997
Department of CNS and Cardiovascular Research (M.V.H.,
C.F.F., D.S.C., E.J.S., H.R.D.),
Department of Allergy (R.L.McL.),
Department of Drug Metabolism and Pharmacokinetics (N.P.Y., K.B.A.),
Schering-Plough Research Institute, Kenilworth, New Jersey
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.
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