Dose dependent pharmacokinetics of nitroglycerin after multiple intravenous infusions in healthy volunteers

Evaluation of the pharmacokinetics of nitroglycerin has been hindered in the past by the lack of specific and sensitive analytical procedures, and the unavailability of parenteral nitroglycerin and infusion sets which did not adsorb nitroglycerin. The purpose for this present study was to determine the pharmacokinetic parameters of nitroglycerin and the dinitrate metabolites after multiple intravenous infusions of nitroglycerin in healthy volunteers. Six volunteers received variable infusion rates of nitroglycerin. Generally, at 0, 40, 80, and 120 min, the infusion rates were adjusted to 10, 20, 40, and 10 micrograms/min, respectively. Plasma samples were drawn and analyzed for nitroglycerin and its 1,2- and 1,3-dinitrate metabolites using capillary GC. Steady-state nitroglycerin plasma concentrations attained at 10, 20, 40, and 10 micrograms/min were 0.44 +/- 0.31, 1.32 +/- 0.71, 4.23 +/- 1.50 and 1.04 +/- 0.43 ng/ml, respectively. As the infusion rate was increased, the steady-state concentrations increased disproportionately. When the dose was decreased from 40 to 10 micrograms/min, the steady-state nitroglycerin concentrations were always higher than those at the initial low infusion rate. Thus, in the majority of subjects, a hysteretic type of response was present. The hysteresis observed in the dose versus steady-state concentration curve may be explained by either end-product inhibition or saturable binding of nitroglycerin to blood vessels. The clearance values (5.5 to 711/min) were very high and far exceed the maximum possible hepatic clearance suggesting that nitroglycerin is metabolized by organs other than liver. Clearance was not directly related to plasma concentrations but was found to decrease to a constant value (approximately 11 +/- 6 l/min) as nitroglycerin concentrations initially increased.