Contribution of isosorbide-5-mononitrate, a major metabolite of isosorbide dinitrate (ISDN), to the hemodynamic effect of ISDN administered orally in conscious dogs.
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.
Kogi
K
K
Research Laboratories, Fukushima, Japan.
Satoh
T
T
D000284:Administration, Oral; D000818:Animals; D001711:Biotransformation; D001794:Blood Pressure / Q000187:drug effects*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D007548:Isosorbide Dinitrate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology*; D008297:Male; D011674:Pulse / Q000187:drug effects*
D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate