Species differences in β-oxidative metabolism of a thromboxane A₂-receptor antagonist [(+)-S-145] in rat, dog and monkey

Abstract

1. The formation of β-oxidized metabolites from (+ )-S-145 [(+ )-(Z)-7-[(lR, IS, 3S, 4S)-3-(benzenesulphonamide)bicyclo-[2.2.l]-hept-2-yl]-5-heptenob acid] by liver homo- genates were compared between rat, dog and monkey. Species differences were found in hepatic β-oxidation capacities. The results agree with the qualitative and quantitative differences in β-oxidized metabolite proportions among these species observed in vivo.

2. The activities of microsomal (+ )-S-145-CoA synthesis, the initial step of the β- oxidation, were determined. Species differences in their intrinsic clearances primarily agreed with those of the β-oxidized metabolite formation.

3. (+ )-S-145-CoA oxidation activities towards (+ )-S-145-CoA by liver homogenates were much higher than the β-oxidized metabolite formation in all species, indicating that formed (+ )-S-145-CoA was immediately β-oxidized in peroxisomes. The species differences were inconsistent with those of β-oxidized metabolite formation in vitro.

4. Therefore, quantitative differences of hepatic (+ )-S-145 β-oxidation capacity in rat, dog and monkey were considered to be mainly due to the species difference in (+ )-S- 145-CoA formation.