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]-β-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.