Nitroglycerin dinitrate metabolites do not affect the pharmacokinetics and pharmacodynamics of nitroglycerin in the dog: a preliminary report

Abstract

Studies were carried out in conscious dogs to determine the effects of 1,2-glyceryl dinitrate (1,2-GDN) and 1,3-glyceryl dinitrate (1,3-GDN) on nitroglycerin (GTN) pharmacokinetics and pharmacodynamics. In the first set of experiments, steady state plasma levels (Css) of either 1,2-GDN or 1,3-GDN in three dogs were rapidly achieved by giving an iv bolus (77 micrograms/kg), followed immediately by an infusion (50 micrograms/min) of the same GDN. A single iv bolus dose of GTN (0.025 micrograms/kg) was given 50 min after beginning the GDN infusion and compared with plasma concentrations following a similar GTN dose in the absence of dosed GDNs. No significant differences in GTN AUC (p > 0.9) and CL(app) (p > 0.7) were found. In a second set of experiments, an infusion of nitroglycerin was begun in each of 4 dogs and continued for 160 min at an infusion rate of 100 micrograms/min. Steady state concentrations of GTN were achieved within 100 min, at which time the dog received, simultaneously, an iv bolus dose (5.14 mg) of one of the GDNs and an infusion dose (100 micrograms/min) of the same GDN. For both dinitrate metabolites no significant differences (p > 0.5) were found between control and interaction arterial and venous clearances, although venous GTN clearances tended to decrease in the presence of dosed GDNs. Steady state systolic blood pressure during GDN infusions could be further reduced when GTN doses were administered; however, the steady state systolic blood pressure decrease caused by GTN could not be further reduced by the GDN infusions. Results suggest that the GDNs do not inhibit nitroglycerin metabolism or hemodynamics at the dose levels studied here.