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Vol. 30, Issue 4, 430-437, April 2002
Schering-Plough Research Institute, Kenilworth, New Jersey
Ezetimibe [SCH 58235;
1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone], a selective cholesterol absorption inhibitor, is being developed for
the treatment of primary hypercholesterolemia. The absorption, metabolism, and excretion of ezetimibe were characterized in eight healthy male volunteers in this single-center, single-dose, open-label study. Subjects received a single oral 20-mg dose of
[14C]ezetimibe (~100 µCi) with 200 ml of
noncarbonated water after a 10-h fast. Concentrations of radioactivity
and/or ezetimibe (conjugated and unconjugated) were determined in
plasma, urine, and fecal samples. Ezetimibe was rapidly absorbed and
extensively conjugated following oral administration. The
main circulating metabolite in plasma was SCH 60663 [1-O-[4-[trans-(2S,3R)-1-(4-fluorophenyl)-4-oxo-3-[3(S)-hydroxy-3-(4-fluorophenyl)propyl]-2-azetidinyl]phenyl]-
-D-glucuronic acid], the glucuronide conjugate of ezetimibe. Plasma
concentration-time profiles of unconjugated and conjugated drug
exhibited multiple peaks, indicating enterohepatic recycling.
Approximately 78 and 11% of the administered
[14C]ezetimibe dose were excreted in feces and urine,
respectively, by 240 h after drug administration. Total recovery
of radioactivity averaged 89% of the administered dose. The main
excreted metabolite was the glucuronide conjugate of ezetimibe. The
primary metabolite in urine (0- to72-h composite) was also the
glucuronide conjugate (about 9% of the administered dose). Significant
amounts (69% of the dose) of ezetimibe were present in the feces,
presumably as a result of SCH 60663 hydrolysis and/or unabsorbed drug.
No adverse events were reported in this study. A single 20-mg
capsule of [14C]ezetimibe was safe and well tolerated
after oral administration. The pharmacokinetics of ezetimibe are
consistent with extensive glucuronidation and enterohepatic
recirculation. The primary metabolic pathway for ezetimibe is by
glucuronidation of the 4-hydroxyphenyl group.
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