Species differences in beta-oxidative metabolism of a thromboxane A2-receptor antagonist [(+)-S-145] in rat, dog and monkey.
1. The formation of beta-oxidized metabolites from (+)-S-145 [(+)-(Z)-7-[(1R, 2S, 3S, 4S)-3-(benzenesulphonamide)bicyclo-[2.2.]-hept-2-yl]-5-heptenoic acid] by liver homogenates were compared between rat, dog and monkey. Species differences were found in hepatic beta-oxidation capacities. The results agree with the qualitative and quantitative differences in beta-oxidized metabolite proportions among these species observed in vivo. 2. The activities of microsomal (+)-S-145-CoA synthesis, the initial step of the beta-oxidation, were determined. Species differences in their intrinsic clearances primarily agreed with those of the beta-oxidized metabolite formation. 3. (+)-S-145-CoA oxidation activities towards (+)-S-145-CoA by liver homogenates were much higher than the beta-oxidized metabolite formation in all species, indicating that formed (+)-S-145-CoA was immediately beta-oxidized in peroxisomes. The species differences were inconsistent with those of beta-oxidized metabolite formation in vitro. 4. Therefore, quantitative differences of hepatic (+)-S-145 beta-oxidation capacity in rat, dog and monkey were considered to be mainly due to the species difference in (+)-S-145-CoA formation.
Yamaguchi
Y
Y
Department of ADME and Toxicology for Screening, Developmental Research Laboratories, Shionogi & Co. Ltd, Toyonaka, Osaka, Japan. yoshitaka.yamaguchi@shionogi.co.jp
Touchi
A
A
Baba
T
T
Matsubara
T
T
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000378:metabolism* / Q000493:pharmacokinetics*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism* / Q000493:pharmacokinetics*; D005260:Female; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D008956:Models, Chemical; D010100:Oxygen / Q000378:metabolism*; D011448:Prostaglandin Antagonists / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013045:Species Specificity; D013997:Time Factors
D001643:Bridged Bicyclo Compounds; D005229:Fatty Acids, Monounsaturated; D011448:Prostaglandin Antagonists; D017482:Receptors, Thromboxane; C056566:S 145; D010100:Oxygen