Contribution of Isosorbide-5-Mononitrate, a Major Metabolite of Isosorbide Dinitrate (ISDN), to the Hemodynamic Effect of ISDN Administered Orally in Conscious Dogs

• Published in: Japanese Journal of Pharmacology Vol. 44; no. 3; pp. 249 - 257
• Main Authors: KOGI, Kentaro, SATOH, Tetsuo
• Format: Journal Article
• Language: English; Japanese
• Published: Kyoto The Japanese Pharmacological Society 1987; Japanese Pharmacological Society
• Subjects: Administration, Oral; Animals; Antianginal agents. Coronary vasodilator agents; Biological and medical sciences; Biotransformation; Blood Pressure - drug effects; Cardiovascular system; Dogs; Dose-Response Relationship, Drug; Female; Isosorbide Dinitrate - administration & dosage; Isosorbide Dinitrate - analogs & derivatives; Isosorbide Dinitrate - blood; Isosorbide Dinitrate - pharmacology; Male; Medical sciences; Pharmacology. Drug treatments; Pulse - drug effects; Antianginal agent; Fissipedia; Carnivora; Vertebrata; Mammalia; Animal; Oral administration; Circulatory system; Pharmacokinetics; Dog; Activity metabolism relation
• ISSN: 0021-5198; 1347-3506
• DOI: 10.1254/jjp.44.249

This study was designed to determine the extent, to which isosorbide-5-mononitrate (5-ISMN) contributes to the hemodynamic effect of isosorbide dinitrate (ISDN) in conscious dogs. Test drugs (ISDN or 5-ISMN) were given orally. Either ISDN or 5-ISMN produced a decrease in blood pressure dose-dependently, the decrease in pulse pressure being specific; the pattern of blood pressure change induced by ISDN or 5-ISMN was different from that induced by nifedipine or prazosin. The effect of ISDN (2 mg/kg) was almost equivalent to that of 5-ISMN (4 mg/kg) and the effect of ISDN (4 mg/kg) to that of 5-ISMN (8 mg/kg). After administration of ISDN, both ISDN and 5-ISMN appeared in the plasma, and the effect of ISDN well-correlated with the increase in the plasma concentration of 5-ISMN. Contribution of 5-ISMN to the effect of ISDN was estimated to be about 30% from the value of the plasma concentration of 5-ISMN at 3 to 4 hr after administration, when the maximal response to ISDN occurred. Based on the data of the area under the plasma concentration curve of 5-ISMN (from 0 to 10 hr after administration), the fraction of biotransformation to 5-ISMN from ISDN was calculated to be 73.6 to 76.6% (based on moles). Because the ability of 5-ISMN to decrease pulse pressure was about 1 /2 (or 41% based on moles) of that of ISDN, the contribution of 5-ISMN to the effect of ISDN was estimated to be about 30% in total, the value being similar with that estimated at 3 to 4 hr after administration.