METABOLIC-FATE OF A NEW ANTIULCER DRUG (+)-(1R, 4AS, 10AR)-1,2,3,4,4A,9,10,10A-OCTAHYDRO-1,4A-DIMETHYL-7-(1-METHYLETHYL)-6-SULFO-1-PHENANTHRENECARBOXYLIC ACID 6-SODIUM SALT PENTAHYDRATE (TA-2711) .1. DISPOSITION, METABOLISM AND PROTEIN-BINDING IN RATS AND DOGS

Metabolic fate of (+)-(1R,4aS,10aR)-1,2,3,4,4a,9,10,10a-octahydro-1,4a-dimethyl-7-(1-methyl-ethyl)-6-sulfo-1-phenanthrenecarboxylic acid 6-sodium salt pentahydrate (TA-271 1), a new anti-ulcer drug, was studied in animals using C-14-TA-271 1. The absorption was estimated to be 3.4-7.0% of dose in rats. The plasma radioactivity after oral dosing peaked at 5-6 h in rats and at 2 h in dogs, and their elimination half lives (beta) were about 120-130 h. After oral or intravenous administration of TA-2711 to rats, the concentrations of radioactivity in most of the tissues were much lower than that in the plasma, indicating the low transfer of TA-2711 into the tissues from the plasma. In whole body autoradiograms of rats, most of the radioactivity given orally was localized in the gastrointestinal tract. Almost all the radioactivity given orally was excreted to the feces while the urinary excretion was extremely low. The sole and slight metabolite, glucuronide of TA-271 1, was detected only in the urine of rats and dogs after oral dosing. During the consecutive oral dosing once a day for 21 d to rats, the plasma levels attained the steady state after administration of drug 7-10 more times. After the final dosing, the patterns of disappearance of radioactivity in the plasma were similar to those in the tissues, and the tissue/plasma ratios of the concentrations were similar to those after single dosing, suggesting no accumulation in rat tissues. More than 96% and about 85% of TA-2711 was bound in vitro to human and rat serum proteins, mainly albumin, respectively. No radioactivity was found in fetus and milk of rats given oral administration.