Pedersen A K, FitzGerald G A
J Pharm Sci. 1985 Feb;74(2):188-92. doi: 10.1002/jps.2600740217.
Inhibition of endogenous prostacyclin and thromboxane biosynthesis by aspirin is critically dose-dependent in humans. Gastrointestinal and hepatic hydrolysis may limit systemic availability of aspirin, especially in low doses, perhaps contributing to the biochemical selectivity of aspirin. Existing analytical methods do not permit determination of systemic bioavailability when low (less than 100 mg) doses of aspirin are administered. Deuterium-labeled aspirin (2-acetoxy[3,4,5,6-2H4]benzoic acid) was synthesized from salicylic acid by catalytic exchange and subsequent acetylation. Analysis of the compounds as benzyl esters by GC-MS followed extractive alkylation from plasma. Heptadeuterated compounds were used as internal standards. Simultaneous administration of tetradeuterated aspirin intravenously with native aspirin orally to anesthetized dogs permitted kinetic studies of both aspirin and salicylic acid. The sensitivity of the method is superior to published methods using HPLC and, thus, more applicable to studies of low dose aspirin. Pulse administration of stable isotope-labeled aspirin permits detailed and repeated studies of dose-related aspirin pharmacokinetics in humans.
阿司匹林对人体内源性前列环素和血栓素生物合成的抑制作用具有关键的剂量依赖性。胃肠道和肝脏的水解作用可能会限制阿司匹林的全身可用性，尤其是低剂量时，这可能导致了阿司匹林的生化选择性。当给予低剂量（小于100毫克）阿司匹林时，现有的分析方法无法测定其全身生物利用度。通过催化交换和随后的乙酰化反应，由水杨酸合成了氘标记的阿司匹林（2-乙酰氧基[3,4,5,6-2H4]苯甲酸）。通过气相色谱-质谱联用仪（GC-MS）将化合物分析为苄酯，随后从血浆中进行萃取烷基化。十七氘代化合物用作内标。将十四氘代阿司匹林静脉注射与天然阿司匹林口服同时给予麻醉犬，可对阿司匹林和水杨酸进行动力学研究。该方法的灵敏度优于已发表的使用高效液相色谱法（HPLC）的方法，因此更适用于低剂量阿司匹林的研究。脉冲给予稳定同位素标记的阿司匹林可对人体中与剂量相关的阿司匹林药代动力学进行详细且重复的研究。
