Pharmacokinetic aspects of isosorbide-5-mononitrate in dogs.

The aim of this study was to determine pharmacokinetic data of isosorbide-5-mononitrate (IS-5-MN) in dogs and to correlate them with the hemodynamic effects of this drug. Beagle dogs (n = 7) were given 3 mg/kg of IS-5-MN, the main metabolite of isosorbide-dinitrate, by i.v. injection and oral administration. At defined times blood samples were withdrawn from the vena cava caudalis for assaying IS-5-MN. In the experiments with oral administration the decrease in systolic blood pressure was monitored as a measure of hemodynamic response. The pharmacokinetic parameters were calculated from the plasma concentrations on the basis of an open two-compartment model. The half-life for the distribution phase was about 6 min, for the elimination phase about 1.5 hr. The latter is about one-third of that obtained in man. From the comparison of the areas under the curve, a bioavailability of 71.5% was estimated. In a second series of investigation dogs were given five different doses of IS-5-MN orally (3.125-50 mg/dog). These experiments showed a rise in the peak plasma concentration and the area under the curve proportional to the dose, whereas the terminal half-life did not differ markedly. A close correlation has been found in both series of investigations between the log concentration and the decrease in blood pressure. The minimum plasma concentration for a hemodynamic effect was estimated to be 100 ng/ml.