Irreversible inhibition of thromboxane (TX) A2 synthesis by Y-20811, a selective TX synthetase inhibitor
| Autor: | Hirotsu Kyouichi, Muramoto Yoshito, Arima Noriyuki, Ochi Hiroshi, Mikashima Hiroshi |
|---|---|
| Rok vydání: | 1992 |
| Předmět: |
Blood Platelets
Male medicine.medical_specialty Time Factors Thromboxane Biochemistry Thromboxane A2 chemistry.chemical_compound Oral administration Internal medicine medicine Animals Platelet Dazoxiben IC50 Pharmacology Imidazoles Rats Inbred Strains Rats Endocrinology chemistry Mechanism of action Thromboxane-A Synthase medicine.symptom Ex vivo |
| Zdroj: | Biochemical Pharmacology. 43:295-299 |
| ISSN: | 0006-2952 |
| Popis: | As Y-20811, sodium (±)-4-[α-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoic 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 T 1 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 ( T 1 2 α = 1.5 hr, T 1 2 β = 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/109 platelets, and the IC50 level was about 600 pg/109 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. |
| Databáze: | OpenAIRE |
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