PHARMACOKINETICS OF ISOSORBIDE-5-MONONITRATE AFTER ORAL-ADMINISTRATION OF AN EXTENDED-RELEASE MONONITRATE FORMULATION VERSUS A STANDARD DINITRATE FORMULATION

The steady-state pharmacokinetic profile of isosorbide-5-mononitrate ( 5-ISMN) after oral administration of an extended-release tablet formul ation of 5-ISMN 60 mg or 120 mg once a day was compared with that afte r administration of isosorbide dinitrate (ISDN) 40 mg every 6 hours, i n a randomized, open-label, three-way crossover trial in 24 healthy me n. After oral administration of extended-release 5-ISMN 60 mg or 120 m g once daily, 5-ISMN was slowly absorbed, reaching mean peak plasma co ncentrations of 557 and 1151 ng/mL, respectively, in approximately 3 h ours. Plasma concentrations of 5-ISMN were dose proportional between 6 0 mg and 120 mg. After oral administration of ISDN 40 mg every 6 hours , a mean peak plasma 5-ISMN concentration of 806 ng/mL was achieved in less than 2 hours (mean time to reach the maximum plasma concentratio n was 1.5 hours). The mean plasma apparent elimination half-life of 5- ISMN was 6.2 hours after extended-release 5-ISMN administration and 7. 1 hours after ISDN. Although the maximum plasma concentration was high er and the minimum plasma concentration was lower after administration of extended-release 5-ISMN 120 mg once daily compared with ISDN 40 mg every 6 hours, there was no significant difference (P > 0.05) in the ''bioavailability'' of 5-ISMN between these two treatments. The most c ommonly reported adverse events in these ''nitrate-naive'' subjects we re headache, dizziness, nausea, and vomiting; these were dose related and their incidence decreased with repeated exposure.