The pharmacokinetics of isosorbide dinitrate (ISDN) and its isomeric mononitrate metabolites (2- and 5-ISMN) were examined in the rat. At a dose of 2 mg/kg, the oral bioavailability of ISDN was found to be about 40%. This finding corrects a previous belief that organic nitrates, when administered via the oral route, are completely metabolized by hepatic first-pass metabolism. ISDN was metabolized exclusively via its mononitrate metabolites, with the 5-ISMN being the principal product (about 90%). The ratio of 2- to 5-ISMN produced was dependent on the route of administration, being 0.18 +/- 0.03 after i.v. dosing and 0.11 +/- 0.03 after oral dosing (both mean +/- S.D.). 2-ISMN was found to decrease the plasma clearance of ISDN; this metabolite interaction occurred when drug and metabolite were administered either at the same or different intravascular sites. 5-ISMN did not affect ISDN plasma clearance when these compounds were administered at different intravascular sites. However, when 5-ISMN and ISDN were given at the same vascular site, a decrease in plasma ISDN clearance was observed. These results provide an interesting example of divergent pharmacokinetic interactions exhibited by two isomeric metabolites.