The absorption, distribution, metabolism and excretion of S-1452 were studied after a single oral or intravenous administration of 14C-labelled compounds at a dose of 5mg/kg in beagle dogs and cynomolgus monkeys.
1. After a single oral or in travenous administration to dogs, taurine-conjugated metabolites were detected in plasma. In monkey plasma at the same dose regimens, high concentrations of glucuronides were found.
2. S-1452 was metabolized mainly by β-oxidation at the α-side chain, hydroxylation of the 5- or 6-position of the bicyclo ring and taurine or glucuronic acid conjugation in dogs and monkeys as well as in rats.
3. The half-lives (t1/2β) of (+)-S-145 in plasma were calculated to be 60min in dogs and 30min in monkeys. These were larger than that observed in rats.
4. The bioavailability of (+)-S-145 after oral administration of 14C-S-1452 was estimated to be approximately 43% in dogs and 5 % in monkeys. The result for dogs suggests that almost no first-pass effect occurred, because absorption after the oral administrtion was estimated to be 40 ?? 50% of the dose in dogs in this study. In contrast, the low bioavailability in monkeys suggests that the first-pass effect of (+)-S-145 in liver or intestinal tracts is very extensive.
