Isosorbide dinitrate (ISDN) (at a concentration of 100 ng/ml) was incubated aerobically at 37 degrees in whole blood from five male and five female normal volunteers. Following incubation of the blood samples for 0, 30, 60, 120, 240 and 360 min, the samples were centrifuged and the plasma was assayed for ISDN. A linear relationship was observed between the logarithm of the concentration of ISDN remaining and incubation time, and there was a significant difference between the T1/2 of ISDN in blood from males (90.6 min) and females (161.4 min). Very little ISDN metabolism was observed when ISDN was incubated with plasma rather than whole blood. When erythrocytes, resuspended in saline, were incubated with ISDN, there was a time-dependent loss of ISDN from the saline incubation medium. Investigation of the soluble fraction obtained after hemolysis of these erythrocytes also showed a time-dependent loss of ISDN. The saline incubation medium contained sufficient concentrations of the two major ISDN metabolites (isosorbide 2- and 5-mononitrate) to account for the observed disappearance of ISDN. The results indicate that ISDN is metabolized in the cellular compartment of blood and that the metabolic rate in males is greater than that in females.