title: Irreversible inhibition of thromboxane (TX) A2 synthesis by Y-20811, a selective TX synthetase inhibitor.
abstract: As Y-20811, sodium (+-)-4-[alpha-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylb+ ++ enzoic acid, has been reported to inhibit serum thromboxane (TX) A2 production with a long duration of action, its mechanism of action was investigated. When [3H]Y-20811 (3 mg/kg) was administered orally to rats, the peak platelet concentration of Y-20811 was obtained 1 hr after the administration, and the T1/2 was 43 hr. The peak plasma concentration of Y-20811 was also obtained 1 hr after administration, but the elimination of Y-20811 from plasma was faster (T1/2 alpha = 1.5 hr, T1/2 beta = 15 hr) than that observed in platelets. Serum TXA2 (estimated as TXB2) production was inhibited significantly from 1 to 72 hr after the oral administration of unlabeled Y-20811 (3 mg/kg), which temporally resembled the change of the platelet Y-20811 concentration. In platelet-rich plasma, [3H]Y-20811 completely inhibited TXA2 production at about 1500 pg/10(9) platelets, and the IC50 level was about 600 pg/10(9) platelets, which was similar to values obtained in ex vivo studies. In addition, inhibition of TXA2 production by Y-20811 still remained after washing the drug-pretreated microsomes, whereas that of dazoxiben completely disappeared. A similar irreversible inhibition of TXA2 production was observed with aspirin. These results suggest that Y-20811 may firmly combine with platelet TX synthetase and may irreversibly inhibit TXA2 production.
authors.affiliation: Research Laboratories, Yoshitomi Pharmaceutical Industries Ltd., Fukuoka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Mikashima
authors.forename: H
authors.initials: H
authors.lastname: Ochi
authors.forename: Y
authors.initials: Y
authors.lastname: Muramoto
authors.forename: K
authors.initials: K
authors.lastname: Hirotsu
authors.forename: N
authors.initials: N
authors.lastname: Arima
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D007093:Imidazoles / Q000097:blood / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013928:Thromboxane A2 / Q000096:biosynthesis*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D013997:Time Factors
chemical_list: D007093:Imidazoles; C049966:Y 20811; D013928:Thromboxane A2; D013930:Thromboxane-A Synthase