DOSE-RELATED KINETICS OF ASPIRIN - PRESYSTEMIC ACETYLATION OF PLATELET CYCLOOXYGENASE
DOSE-RELATED KINETICS OF ASPIRIN - PRESYSTEMIC ACETYLATION OF PLATELET CYCLOOXYGENASE
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DOI：
10.1056/nejm198411083111902
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发表时间：
1984-01-01
影响因子：
158.5
通讯作者：
FITZGERALD, GA
中科院分区：
文献类型：
--
作者：
PEDERSEN, AK;FITZGERALD, GA
当阿司匹林以低剂量口服给药时，全身生物利用度差可能导致其对血栓烷A2形成的明显剂量相关选择性抑制。口服阿司匹林的全身生物利用度对于抑制全身血管内皮细胞合成前列环素是必要的，而血小板对血栓烷A2形成的累积抑制可能发生在系统前（门静脉）循环中。在5名健康志愿者中同时口服未标记的阿司匹林和静脉注射2 H标记的阿司匹林，可以根据标记和未标记物质的血浆药物浓度-时间曲线的比值估计口服剂量的生物利用度。全身生物利用度范围为20、40、325和1300 mg阿司匹林单次口服剂量的48-51%。325 mg单次给药和长期口服给药后的生物利用度相似。在体循环中检测到阿司匹林之前，口服20 mg未标记的阿司匹林后，离体血清中血栓烷B2的形成减少了39%。体外全血中模拟血浆阿司匹林峰值浓度的孵育低估了口服20或40 mg未标记阿司匹林后离体血栓烷B2的抑制作用。这些数据与阿司匹林对血小板的系统前抑制一致，并表明缓慢给予极低剂量的阿司匹林可能会增强生化选择性，从而优化血小板环氧合酶的累积、系统前乙酰化和血栓素形成抑制的条件。
When aspirin is administered by mouth in low doses, poor systemic bioavailability may contribute to its apparent dose-related selective inhibition of thromboxane A2 formation. Systemic bioavailability of orally administered aspirin is necessary to inhibit prostacyclin synthesis by systemic vascular endothelium, whereas cumulative inhibition of thromboxane A2 formation by platelets may occur in the presystemic (portal) circulation. Simultaneous administration of unlabeled aspirin orally and 2H-labeled aspirin i.v. in 5 healthy volunteers permitted an estimation of the bioavailability of an oral dose from the ratio of plasma drug concentration-time curves for the labeled and the unlabeled species. Systemic bioavailability ranged from 48-51% of single oral doses of 20, 40, 325 and 1300 mg of aspirin. Bioavailability was similar after single-dose and long-term oral administration of 325 mg. Thromboxane B2 formation in serum ex vivo after oral administration of 20 mg of unlabeled aspirin was reduced 39% before aspirin was detected in the systemic circulation. Incubation of simulated peak plasma aspirin concentrations in whole blood in vitro underestimated the inhibition of thromboxane B2 ex vivo after oral administration of 20 or 40 mg of unlabeled aspirin. These data are consistent with presystemic inhibition of platelets by aspirin and suggest that biochemical selectivity might be enhanced by slow administration of very low doses of aspirin, thereby optimizing conditions for cumulative, presystemic acetylaton of platelet cyclooxygenase and inhibition of thromboxane formation.