S-8921 (methyl 1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimeth oxy-2- naphthoate, CAS 151165-96-7) is a novel hypocholesterolemic agent which was found to inhibit ileal Na+/bile acid cotransporter. In this report, the pharmacokinetic profile of S-8921 was studied in rats and dogs. After dosing of 14C-S-8921 to rats at 1 to 25 mg/kg as 0.5% methylcellulose (MC) suspension, tmax was observed during 5-6 h, and AUCs increased with the dose, but not proportionally. The elimination half-lives were around 38-41 h for the doses examined. The apparent absorption ratio of 5 mg/kg of 14C-S-8921 as MC suspension was about 14%. Most of the radioactivity (98% of dose) was excreted into the feces and only 1-2% into the urine. Biliary excretion of radioactivity after dosing of 1, 5 or 25 mg/kg was 22, 20, 15%, respectively. Saturation of the absorption process was suggested. Even in case of intravenous dosing, about 88% was excreted into the bile. Enterohepatic circulation of biliary metabolites was also observed in rat. Its extent was small (6%), but, it may be contribute to the slow elimination of S-8921 from rat. The highest radioactivity was observed in the liver, with other tissues showing similar radioactivity profiles to that of plasma. The elimination half-lives of radioactivity from tissues were very long, e.g. 68 h for the liver and 58 h for the kidney. After 14 days multiple dosing, most tissues showed about two times higher radioactivity than that after a single dose. The simulation curves of liver and plasma showed a good fit with those of the observed values. These results suggested that there is no serious accumulation of radioactivity in tissues by multiple dosing of 14C-S-8921 in rats. The plasma radioactivity after oral dosing of 5 mg/kg of 14C-S-8921 to dogs as an MC suspension reached maximum concentration (c.a. 33 ng/ml) at 2 h, then decreased very slowly with a half-life of 169 h. The apparent absorption ratio was 4.6% for MC suspension. The excretion of radioactivity into bile, feces and urine after oral dosing of 14C-S-8921 at 5 mg/kg as an MC suspension were 3.0%, 94.6% and 0.3%, respectively. Even in the case of intravenous dosing, urinary excretion was very small (2.2%) and most of the radioactivity was excreted very slowly into the feces. The major metabolite of S-8921 in rat bile was its glucuronide. Other minor metabolites identified were the demethylated forms of 7-methoxy and 4'-methoxy moieties of S-8921. They were also excreted into bile as their glucuronides.