Haefeli W E, Gumbleton M, Benet L Z, Hoffman B B, Blaschke T F
Department of Medicine, Stanford University School of Medicine, CA.
Clin Pharmacol Ther. 1992 Dec;52(6):590-6. doi: 10.1038/clpt.1992.196.
Independent of the route of nitroglycerin administration, substantial amounts of 1,2-glyceryl dinitrate (1,2-GDN) and 1,3-glyceryl dinitrate (1,3-GDN) metabolites accumulate in humans. Thus far their pharmacologic activity in comparison to nitroglycerin in humans is unknown. To compare the venodilatory potency of nitroglycerin and of 1,2-GDN and 1,3-GDN in vivo, cumulative dose-response curves were established in nine healthy volunteers by use of the dorsal hand vein compliance technique. Separated by a washout period, two of the three venodilators were infused in randomized order after preconstriction with phenylephrine. Values for maximum vasodilation were similar for all compounds: nitroglycerin, 109%; 1,2-GDN, 100%; and 1,3-GDN, 106%. The respective values for the dose rate exerting 50% of maximum vasodilation were 5.1, 43, and 60 ng/min, indicating that the dinitrates were about 10 times less potent than nitroglycerin (p < 0.001) but not significantly different from each other. The findings support the hypothesis that activity of nitroglycerin metabolites is related to the number of nitrate groups in the molecule and are in agreement with lower dinitrate potencies found in animal experiments.
无论硝酸甘油的给药途径如何，大量的1,2-二硝酸甘油酯（1,2-GDN）和1,3-二硝酸甘油酯（1,3-GDN）代谢物都会在人体内蓄积。到目前为止，它们与硝酸甘油相比在人体中的药理活性尚不清楚。为了比较硝酸甘油、1,2-GDN和1,3-GDN在体内的静脉扩张效力，利用手背静脉顺应性技术在9名健康志愿者身上建立了累积剂量-反应曲线。在洗脱期后，在用去氧肾上腺素预收缩后，以随机顺序输注三种静脉扩张剂中的两种。所有化合物的最大血管舒张值相似：硝酸甘油为109%；1,2-GDN为100%；1,3-GDN为106%。产生50%最大血管舒张的剂量率的相应值分别为5.1、43和60 ng/min，这表明二硝酸酯的效力比硝酸甘油低约10倍（p < 0.001），但彼此之间无显著差异。这些发现支持了以下假设，即硝酸甘油代谢物的活性与分子中的硝酸酯基团数量有关，并且与在动物实验中发现的二硝酸酯较低的效力一致。
