血栓素A2合成酶特异性抑制剂UK-38485（达美格雷）的药理学

Pharmacology of UK-38485 (dazmegrel), a specific inhibitor of thromboxane A2 synthetase.

作者信息

Rebec M V, Skrinska V A

机构信息

Cleveland Research Institute, Ohio 44115.

出版信息

Prostaglandins Leukot Essent Fatty Acids. 1989 Dec;38(3):207-12. doi: 10.1016/0952-3278(89)90074-4.

DOI:10.1016/0952-3278(89)90074-4

PMID:2622975

Abstract

Thromboxane A2 (TXA2) synthesis in rabbit and human platelet rich plasma (PRP) was inhibited in a dose-dependent manner by UK-38485 (dazmegrel) when the PRP was aggregated with collagen, arachidonic acid and ADP. The level of inhibition was time-dependent. That is, the dose-response curves shifted to lower concentrations with increasing incubation times with UK-38485 prior to addition of aggregation agents. Following bolus intravenous injections of UK-38485 in rabbits, the elimination from serum fitted a 3-exponential curve. The terminal elimination phase had a half-life of 69.8 +/- 3.8 min. Oral treatment of rabbits with UK-38485 for 2 weeks showed that animals with serum concentrations of 0.358 +/- 0.091 microgram/ml of the inhibitor had TXA2 synthesis inhibited in serum by 83.8 +/- 7.1%. This corresponded to animals which were treated with 20 mg/kg/day of the inhibitor.

摘要

当富含血小板的血浆（PRP）与胶原蛋白、花生四烯酸和二磷酸腺苷（ADP）聚集时，UK-38485（达美格雷）以剂量依赖的方式抑制兔和人PRP中血栓素A2（TXA2）的合成。抑制水平呈时间依赖性。也就是说，在添加聚集剂之前，随着与UK-38485孵育时间的增加，剂量反应曲线向较低浓度偏移。在兔静脉推注UK-38485后，血清中的消除符合三指数曲线。终末消除相的半衰期为69.8±3.8分钟。用UK-38485对兔进行为期2周的口服治疗表明，血清中抑制剂浓度为0.358±0.091微克/毫升的动物血清中TXA2合成被抑制了83.8±7.1%。这相当于用20毫克/千克/天的抑制剂治疗的动物。