Plasma concentrations of isosorbide-5-mononitrate (5-ISMN) (TY-10368) measured: (1) after oral doses of 10 mg at fasting or at 1.5 hr after meal in 3 subjects with one week between dosing sessions, (2) after oral doses of 10, 20 40 mg in 6 subjects and (3) after repeated oral doses of 20 mg at 12-hr intervals 84 hr in 6 subjects. Food intake reduced the peak plasma concentrations of ISMN, but did not affect the extent of bioavailability from oral dosing after an overnight fast. Maximum plasma concentrations were achieved within the same range time after all doses: an average of 1.7 hr±0.2 (SD; non-fasting). The pharmaco-kinetics showed dose-lineality, since the peak plasma concentrations and the total area under the curve (AUC) were proportional to dose administered. The elim ination half-lives after administration of all doses were in the range of 5-6 hr, with narrow interindividual variation. The total amounts of free and conjugated 5-ISMN excreted into the urine over 60 hr were proportional to dose administered within a range of 22-36%, and only a trace amount was detected at 24 hr after dose.
Repeated administration at 12-hr intervals during 84 hr did not increase the minimal plasma concentration or elimination half-life without significant increase of time to peak plasma concentration.
Whereas the diastolic blood pressure did not change systematically, average falls in the systolic blood pressure of 6.2%, 10.3% and 12.3% were observed at the time of the peak plasma levels after single oral dose of 10, 20 and 40 mg, respectively. There was no significant correlation between maximum plasma 5-ISMN levels and corresponding systolic blood pressure reduction.
The plasma cyclic GMP concentrations determined when the peak 5-ISMN plasma levels were achieved or when the maximal systolic blood pressure reductions were noted, decreased significantly after oral doses of 20 mg, but the highest dose did not change the plasma cyclic GMP levels significantly.
All subjects complained of a headache or felt heavy-headedness which did not seem to be dose-dependent, and mentioned no symptoms at 24 hr after TY-10368 administration.
