PHARMACOKINETICS AND PHARMACODYNAMICS OF NITROGLYCERIN AND ITS DINITRATE METABOLITES IN CONSCIOUS DOGS - INTRAVENOUS-INFUSION STUDIES

Intravenous infusions of nitroglycerin (GTN), 1,2-glyceryl dinitrate ( 1,2-GDN), and 1,3-glyceryl dinitrate (1,3-GDN) were given to four cons cious dogs at 10 mug/min, 30 mug/min, 50 mug/min, and 70 mug/min of GT N and 20 mug/min and 100 mug/min of GDNs. The steady state plasma conc entrations (Css) of GTN were reached after about 60 min whereas for 1, 2-GDN and 1,3-GDN the Css were reached at about 150 min after the infu sion began. Except for one dog, the Css of GTN were not proportional t o infusion rate, however, all dogs together showed a good linear relat ionship between Css of GTN and infusion rates with an average correlat ion coefficient of 0.917 +/- 0.102. Large variability in GTN clearance after various infusion rates was observed in all dogs. The Css ratios of 1.2-GDN/GTN and 1,3-GDN/GTN yield overall averages of 31.5 +/- 17. 2 and 5.47 +/- 3.19, respectively. Average Css ratios of metabolites 1 ,2-GDN/1,3-GDN were 5.78 +/- 1.23. This ratio is different from those obtained after iv bolus and oral dosing indicating that the biotransfo rmation of GTN to 1,2-GDN and 1,3-GDN differs for each dosing route. T he clearances for 1,2-GDN and 1,3-GDN were not changed over the dose r ange of 20 mug/min to 100 mug/min. Terminal half-lives of 1,2-GDN and 1,3-GDN postinfusion were similar to those values obtained after a sin gle bolus dose (45 min). It appears that all the GTN dose at steady st ate can be accounted for by the formation of measurable 1,2-GDN and 1, 3-GDN. Large intra- and interdog variations in systolic blood pressure decrease (SPD) following infusions of GTN were observed, however, all dogs showed a clear systolic blood pressure decrease when the highest infusion rate (70 mug/min) was given. No significant systolic blood p ressure drop was detected following 20 mug/min infusions of 1,2-GDN or 1.3-GDN. It was clear that systolic blood pressure in all dogs decrea sed following 100 mug/min infusions of 1,2-GDN or 1,3-DGN. When SPD va lues were plotted vs log GTN concentrations following the infusion of 70 mug/min of GTN in all four dogs, a conterclockwise hysteresis was o bserved indicating the significant contribution of the active dinitrat e metabolites to GTN pharmacodynamics.