![]() ![]() At least six different compounds have been detected in urine, with about 2% of the dose excreted as the unchanged drug and at least five metabolites. ![]() ISMN is cleared by denitration to isosorbide and glucuronidation as the mononitrate, with 96% of the administered dose excreted in the urine within 5 days and only about 1% eliminated in the feces. ISMN is primarily metabolized by the liver, but unlike oral Isosorbide dinitrate, it is not subject to first-pass metabolism. ISMN is approximately 5% bound to human plasma proteins and is distributed into blood cells and saliva. After intravenous administration, ISMN is distributed into total body water in about 9 minutes with a volume of distribution of approximately 0.6 to 0.7 L/kg. Isosorbide mononitrate extended-release tablets during long-term use over 42 days dosed at 120 mg once daily continued to improve exercise performance at 4 hours and at 12 hours after dosing but their effects (although better than placebo) are less than or, at best, equal to the effects of the first dose of 60 mg.Īfter oral administration of ISMN as a solution or immediate-release tablets, maximum plasma concentrations of ISMN are achieved in 30 to 60 minutes, with an absolute bioavailability of approximately 100%. Only after nitrates have been absent from the body for several hours has their antianginal efficacy been restored. Attempts to overcome tolerance by dose escalation, even to doses far in excess of those used acutely, have consistently failed. In the large majority of these trials, active agents were indistinguishable from placebo after 24 hours (or less) of continuous therapy. Several well-controlled clinical trials have used exercise testing to assess the antianginal efficacy of continuously delivered nitrates. This strategy is inappropriate for organic nitrates. Dosing regimens for most chronically used drugs are designed to provide plasma concentrations that are continuously greater than a minimally effective concentration. ![]()
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