Torfgård K E, Ahlner J, Axelsson K L, Norlander B, Bertler A
Department of Clinical Pharmacology, Faculty of Health Sciences, University Hospital, Linköping, Sweden.
Drug Metab Dispos. 1992 Jul-Aug;20(4):553-8.
The tissue distribution of glyceryl trinitrate (GTN) and its two dinitrate metabolites 1,2-glyceryl dinitrate (1,2-GDN) and 1,3-glyceryl trinitrate (1,3-GDN), was studied in GTN-tolerant and nontolerant male Sprague-Dawley rats. The concentrations of GTN, 1,2-GDN, and 1,3-GDN were measured in plasma, heart, brain, liver, aortic tissue, and adipose tissue at various time points after a subcutaneous dose of GTN (50 mg/kg). At the first time point (5 hr), concentrations of GTN, 1,2-GDN, and 1,3-GDN in plasma were equal for tolerant and nontolerant rats, but the elimination rate was altered for the tolerant rats as compared with nontolerant rats. In adipose tissue, the concentration of GTN was significantly higher as compared with concentrations of the dinitrate metabolites. In contrast, the other tissues studied showed significantly higher concentrations of the GDNs when compared with GTN. The 1,3-GDN/1,2-GDN ratio decreased with time for both tolerant and nontolerant rats. This study indicates that long-term GTN administration results not only in tolerance development, but also in altered pharmacokinetics of GTN, 1,2-GDN, and 1,3-GDN. The results also show that the 1,3-GDN/1,2-GDN ratio is dependent on the GTN concentration.
在对硝酸甘油（GTN）耐受和不耐受的雄性Sprague-Dawley大鼠中，研究了硝酸甘油及其两种二硝酸盐代谢产物1,2-甘油二硝酸盐（1,2-GDN）和1,3-甘油二硝酸盐（1,3-GDN）的组织分布。皮下注射硝酸甘油（50 mg/kg）后，在不同时间点测量血浆、心脏、大脑、肝脏、主动脉组织和脂肪组织中GTN、1,2-GDN和1,3-GDN的浓度。在第一个时间点（5小时），耐受和不耐受大鼠血浆中GTN、1,2-GDN和1,3-GDN的浓度相等，但与不耐受大鼠相比，耐受大鼠的消除率发生了改变。在脂肪组织中，与二硝酸盐代谢产物的浓度相比，GTN的浓度显著更高。相反，与GTN相比，其他研究组织中GDNs的浓度显著更高。对于耐受和不耐受大鼠，1,3-GDN/1,2-GDN比值均随时间下降。本研究表明，长期给予GTN不仅会导致耐受性的产生，还会改变GTN、1,2-GDN和1,3-GDN的药代动力学。结果还表明，1,3-GDN/1,2-GDN比值取决于GTN浓度。
