Ritter J M, Doktor H S, Benjamin N, Barrow S E, Stewart-Long P
Department of Clinical Pharmacology, UMDS, Guy's Hospital, London.
Adv Prostaglandin Thromboxane Leukot Res. 1991;21A:351-4.
Twenty four healthy men were treated with GR32191, a thromboxane receptor antagonist with a long duration of action, in a double blind placebo-controlled crossover study. Platelet aggregation in response to a thromboxane (TX) mimetic (U46619) was studied turbidometrically using platelet rich plasma (PRP) prepared 12 h after dosing (80 mg po) and 1.5 h after a second dose (40 mg po). To determine whether the long lasting inhibition caused by GR32191 is associated with persistent inhibitory activity in plasma (from residual drug or from an active metabolite), platelet poor plasma (PPP) from treated subjects was mixed with PRP from placebo treated controls. 12 h after dosing this caused 40-80% inhibition, consistent with the plasma concentration of GR32191. Inhibition of U46619 in PRP from GR32191 treated subjects mixed with PPP from controls was even greater (essentially 100%). We conclude that the prolonged activity of GR32191 is due in part to a reduction in available thromboxane receptors and in part to its persistence in plasma for longer than had previously been appreciated.
在一项双盲安慰剂对照交叉研究中，24名健康男性接受了GR32191（一种作用持续时间长的血栓素受体拮抗剂）治疗。使用给药（口服80毫克）12小时后和第二次给药（口服40毫克）1.5小时后制备的富血小板血浆（PRP），通过比浊法研究了对血栓素（TX）模拟物（U46619）的血小板聚集反应。为了确定GR32191引起的持久抑制是否与血浆（来自残留药物或活性代谢物）中的持续抑制活性相关，将治疗受试者的乏血小板血浆（PPP）与安慰剂治疗对照的PRP混合。给药12小时后，这导致了40 - 80%的抑制，与GR32191的血浆浓度一致。将GR32191治疗受试者的PRP与对照的PPP混合后，对U46619的抑制作用甚至更大（基本上为100%）。我们得出结论，GR32191的延长活性部分归因于可用血栓素受体的减少，部分归因于其在血浆中的持续时间比以前认识到的更长。
