The absorption, distribution, metabolism and excretion of S-1452, a new thromboxane A2 receptor antagonist, were studied after a single oral or intravenous administration of 14C-labelled compounds at a dose of 5mg/kg to fasted and non-fasted rats. Also, using 3H-(+)-S-145·Na, in vitro binding to serum protein was investigated in experimental animals and humans.
1. After oral administration, 14C-S-1452 was almost completely absorbed in both fasted and non-fasted rats, and approximately 90% of the dosed radioactivity was excreted into the bile.
2. Plasma concentration profiles of radioactivity, (+)-S-145 and its metabolites after an intravenous administration to fasted rats were similar to those found with non-fasted rats.
3. The bioavailability of (+)-S-145 after an oral administration of 14C-S-1452 was estimated to be approximately 70% in fasted and 30% in non-fasted rats. This suggests that the hepatic first-pass effect of (+)-S-145 in rats is extensive and that it is influenced by the gastric emptying rate.
4. After oral administration of 14C-S-1452, the plasma concentration of dihydrobisnor was higher than bisnor. This suggests that the reduction of the ethylene bond at the α-side chain of (+)-S-145 occurs predominantly rather than β-oxidation.
5. The major metabolites excreted in urine were 5-OH-tetranor and 6-OH-tetranor, which were hydroxylated at the 5- or 6-position of bicyclo ring, respectively. In the bile, main fraction of the radioactivity was excreted as conjugated metabolites, with more taurine conjugates than glucuronides.
6. The in vitro binding to serum protein of (+)-S-145 accounted for more than 95% in all species studied.
