| Abstract: | In a crossover design four male dogs were given orally or i.v. 14C]isosorbide dinitrate (ISDN) or 14C]isosorbide-2-mononitrate (2-ISMN) at a dose of 1 mg kg-1 (70-80 microCi). Virtually all of the oral dose was absorbed and all of the radioactivity was excreted in the urine. The profile of serum radioactivity was similar after all drug administrations. ISDN was rapidly denitrated, giving rise to isosorbide-5-mononitrate (5-ISMN) as a major metabolite, and 2-ISMN as a minor metabolite. The apparent elimination half-life from serum of 2-ISMN and 5-ISMN was 2-3 h. More than 50% of the serum radioactivity after 14C]2-ISMN was due to unchanged drug. The apparent volume of distribution of 2-ISMN averaged 8.3 litres. The results show that, in contrast to ISDN, administration of 2-ISMN resulted in relatively high unchanged drug levels in the serum; the disposition of radioactivity after 14C]ISMN was however similar to that after 14C]ISDN. The findings support the concept that the concentrations of ISDN, 2-ISMN and 5-ISMN in the blood are inversely related to the rates of denitration, and that the vascular activity of the nitrates of isosorbide relates to the rates of their dinitration. |
