DISPOSITION AND METABOLISM OF THE NEW HYPOCHOLESTEROLEMIC COMPOUND S-8921 IN RATS AND DOGS

S-8921 (methyl )-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2- naph thoate, CAS 151165-96-7) is a novel hypocholesterolemic agent which wa s found to inhibit ileal Na+/bile acid cotransporter In this report, t he pharmacokinetic profile of S-8921 was studied in rats and dogs. Aft er dosing of C-14-S-8921 to rats at 1 to 25 mg/kg as 0.5% methylcellul ose (MC) suspension, t(max) was observed during 5-6 h, and AUCs increa sed with the dose, but not proportionally. The elimination half-lives were around 38-41 h for the doses examined. The apparent absorption ra tio of 5 mg/kg of C-14-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 o f 1, 5 or 25 mg/kg was 22, 20, 15%, respectively. Saturation of the ab sorption process was suggested. Even in case of intravenous dosing, ab out 88% was excreted into the bile. Enterohepatic circulation of bilia ry metabolites was also observed in rat. Its extent was small (6%), bu t, it may be contribute to the slow elimination of S-8921 from rat. Th e highest radioactivity was observed in the liver, with other tissues showing similar radioactivity profiles to that of plasma. The eliminat ion 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 af ter a single dose. The simulation curves of liver and plasma showed a good fit with those of the observed values. These results suggested th at there is no serious accumulation of radioactivity in tissues by mul tiple dosing of C-14-S-8921 in rats. The plasma radioactivity after or al dosing of 5 mg/kg of C-14-S-8921 to dogs as an MC suspension reache d maximum concentration (c.a. 33 ng/ml) at 2 h, then decreased very sl owly with a half-life of 169 h. The apparent absorption ratio was 4.6% for MC suspension. The excretion of radioactivity into bile, feces an d urine after oral dosing of C-14-S-8921 at 5 mg/kg as an MC suspensio n were 3.0%, 94.6% and 0.3%, respectively. Even in the case of intrave nous dosing, urinary excretion was very small (2.2%) and most of the r adioactivity was excreted very slowly into the feces. The major metabo lite of S-8921 in rat bile was its glucuronide. Other minor metabolite s identified were the demethylated forms of 7 methoxy and 4'-methoxy m oieties of S-8921. They were also excreted into bile as their glucuron ides.