Mayer P R, Lubawy W C, McNamara P J, Kostenbauder H B
J Pharm Sci. 1983 Jul;72(7):785-9. doi: 10.1002/jps.2600720717.
The uptake and metabolism of isosorbide dinitrate was investigated in the recirculating isolated perfused rabbit lung and in lung homogenate 9000 X g supernatant. Concentration versus time profiles from the isolated lung experiments indicate rapid metabolism of isosorbide dinitrate and corresponding increases in the metabolites 5-isosorbide mononitrate, 2-isosorbide mononitrate, and isosorbide. The data suggest that the mononitrates formed in the lung tissue were converted to isosorbide at an extraordinarily high rate. Surprisingly, the rate of appearance of completely denitrated isosorbide was greater when isosorbide dinitrate was administered to the lung than when the mononitrate metabolites of isosorbide dinitrate were administered. The results suggest rapid metabolism of a substantial portion of the mononitrates formed endogenously from isosorbide dinitrate before partitioning of mononitrates into the perfusion medium could occur. The metabolism of isosorbide dinitrate in lung homogenate 9000 X g supernatant exhibited a metabolic scheme kinetically different from the intact lung studies, as isosorbide was formed slowly from a mononitrate intermediate and not by a near-simultaneous cleavage of both nitrate ester groups. Intravascular multiple-dose studies did not demonstrate any inhibition between isosorbide dinitrate and the mononitrates.
在循环式离体灌注兔肺及肺匀浆9000×g 上清液中研究了硝酸异山梨酯的摄取和代谢。离体肺实验得到的浓度-时间曲线表明硝酸异山梨酯迅速代谢，代谢产物5-单硝酸异山梨酯、2-单硝酸异山梨酯和异山梨醇相应增加。数据表明肺组织中形成的单硝酸酯以极高的速率转化为异山梨醇。令人惊讶的是，将硝酸异山梨酯给予肺时，完全脱硝的异山梨醇的出现速率比给予硝酸异山梨酯的单硝酸酯代谢产物时更快。结果表明，在单硝酸酯分配到灌注介质之前，由硝酸异山梨酯内源性形成的大部分单硝酸酯迅速代谢。肺匀浆9000×g 上清液中硝酸异山梨酯的代谢表现出一种动力学上与完整肺研究不同的代谢模式，因为异山梨醇是由单硝酸酯中间体缓慢形成的，而不是通过两个硝酸酯基团几乎同时裂解形成的。血管内多剂量研究未显示硝酸异山梨酯与单硝酸酯之间有任何抑制作用。
