Fung H L, Sutton S C, Kamiya A
J Pharmacol Exp Ther. 1984 Feb;228(2):334-41.
Recent reports have suggested that the unusual pharmacokinetics observed for nitroglycerin (NTG) and isosorbide dinitrate (ISDN) may be partially explained by extensive uptake and/or metabolism of these drugs by vascular and other extrahepatic tissues. Using the rat as an animal model, this hypothesis was examined by in vivo intravessel NTG and [14C]ISDN infusion and injection into various vessel segments, viz. the femoral vein, inferior vena cava [IVC: lower, middle and upper) and the aorta. NTG and [14C]ISDN concentrations were determined in these blood vessels and in plasma. Blood vessel segments nearest the input site had the greatest amounts of nitrate, whereas segments further away from the input site had progressively less nitrate, with the exception of aorta, which appeared to take up NTG less extensively, on a per weight of vessel basis, than the IVC. Blood vessel NTG concentrations (nanogram per gram) were generally higher (10-fold) and declined about twice as slowly as NTG plasma concentrations (nanograms per milliliter). [14C]NTG and [14C]ISDN were also incubated with cofactors in IVC, aorta, abdominal muscle, lung and liver. The amounts of nitrate metabolites formed from parent drug were larger in each extrahepatic tissue incubation than in the controls (P less than .05). The results are consistent with the hypothesis that vascular and other extrahepatic tissues can take up and/or metabolize organic nitrates. The data appear to provide a partial explanation for the large systemic clearance seen with nitrates and appear consistent with existing mechanistic hypotheses for the vascular action of these compounds.
最近的报告表明，硝酸甘油（NTG）和异山梨醇二硝酸酯（ISDN）所观察到的异常药代动力学现象，可能部分归因于这些药物被血管及其他肝外组织大量摄取和/或代谢。以大鼠作为动物模型，通过体内血管内输注NTG和[14C]ISDN并将其注射到不同血管段，即股静脉、下腔静脉（下腔静脉：下部、中部和上部）以及主动脉，来检验这一假设。测定了这些血管和血浆中的NTG和[14C]ISDN浓度。最靠近输入部位的血管段硝酸盐含量最高，而离输入部位较远的血管段硝酸盐含量逐渐减少，但主动脉除外，按每克血管计算，主动脉对NTG的摄取似乎不如下腔静脉广泛。血管中NTG浓度（纳克/克）通常较高（高10倍），下降速度约为NTG血浆浓度（纳克/毫升）的一半。[14C]NTG和[14C]ISDN还与辅因子在体外下腔静脉、主动脉、腹肌、肺和肝脏中进行孵育。在每个肝外组织孵育中，由母体药物形成的硝酸盐代谢物的量均大于对照组（P<0.05）。结果与血管及其他肝外组织能够摄取和/或代谢有机硝酸盐的假设一致。这些数据似乎为硝酸盐所具有的较大全身清除率提供了部分解释，并且似乎与这些化合物血管作用的现有机制假设相符。
