The organic nitrate 1,3-glyceryl dinitrate (1,3-GDN) is one of the primary dinitrate metabolites of the antianginal agent nitroglycerin (GTN). Investigational New Drug Approval was sought to administer oral solution doses of 1,3-GDN to a small number (n = 3) of healthy volunteers; each subject receiving three doses at 1.2, 2.4, and 3.6 mg. With volunteers confined to a semirecumbent posture for the duration of each treatment (4-hr period postdose), diastolic blood pressure (DBP) was recorded and plasma samples collected for 1,3-GDN concentration analysis. Appreciable concentration-related decreases in DBP were observed, with maximal decreases from predose baseline values approximating 11 to 25 mm Hg. For each subject parametric pharmacodynamic modeling was performed with simultaneous analysis utilizing the DBP vs. time data from all three doses; an inhibitory Emax pharmacodynamic model was adopted. The temporal relationship between plasma 1,3-GDN concentrations and DBP displayed rapid equilibration. For subjects 1, 2 and 3, respectively, Emax was predicted as 12.9, 23.4, and 29.7 mm Hg, representing 21.5, 31.6, and 39.5% decreases in DBP from predose baseline values; plasma concentrations at half Emax (C50) were 2.75, 2.43, and 5.93 micrograms/L. Utilizing pharmacokinetic-pharmacodynamic modeling, 1,3-GDN plasma concentrations appear to relate to a systemic "effect measure" that is mechanistically representative of the therapeutic actions of organic nitrates as peripheral vasodilators. The establishment of a GDN plasma concentration-effect relationship together with the relatively high plasma levels of GDN achieved following GTN dosing supports the hypothesis that the GDNs contribute significantly to the hemodynamic effect observed with GTN.