The volume of distribution of isosorbide mononitrate is approximately 0.6 L/Kg, and less than 4% is bound to plasma proteins. It is cleared from the serum by denitration to isosorbide; glucuronidation to the mononitrate glucuronide; and denitration/hydration to sorbitol. None of these metabolites is vasoactive. Less than 1% of administered isosorbide mononitrate is eliminated in the urine.

The overall elimination half-life of isosorbide mononitrate is about 5 hours; the rate of clearance is the same in healthy young adults, in patients with various degrees of renal, hepatic, or cardiac dysfunction, and in the elderly. In a single-dose study, the pharmacokinetics of isosorbide mononitrate were dose-proportional up to at least 60 mg.

Pharmacokinetics and Metabolism

Extended Release Tablets

After intravenous administration, isosorbide mononitrate is distributed into total body water in about 9 minutes with a volume of distribution of approximately 0.6-0.7 L/kg. Isosorbide mononitrate is approximately 5% bound to human plasma proteins and is distributed into blood cells and saliva. Isosorbide mononitrate is primarily metabolized by the liver, but unlike oral isosorbide dinitrate, it is not subject to first-pass metabolism. Isosorbide mononitrate 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. 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. The metabolites are not pharmacologically active. Renal clearance accounts for only about 4% of total body clearance. The mean plasma elimination half-life of isosorbide mononitrate is approximately 5 hours.

The disposition of isosorbide mononitrate in patients with various degrees of renal insufficiency, liver cirrhosis, or cardiac dysfunction was evaluated and found to be similar to that observed in healthy subjects. The elimination half-life of isosorbide mononitrate was not prolonged, and there was no drug accumulation in patients with chronic renal failure after multiple oral dosing.

The pharmacokinetics and/or bioavailability of isosorbide mononitrate extended release tablets have been studied in both normal volunteers and patients following single- and multiple-dose administration. Data from these studies suggest that the pharmacokinetics of isosorbide mononitrate administered as isosorbide mononitrate extended release tablets are similar between normal healthy volunteers and patients with angina pectoris. In single- and multiple-dose studies, the pharmacokinetics of isosorbide mononitrate were dose proportional between 30 mg and 240 mg.

In a multiple-dose study, the effect of age on the pharmacokinetic profile of isosorbide mononitrate extended release tablets 60 mg and 120 mg (2 ´ 60 mg) tablets was evaluated in subjects ³45 years. The results of that study indicate that there are no significant differences in any of the pharmacokinetic variables of isosorbide mononitrate between elderly (³65 years) and younger individuals (45-64 years) for the isosorbide mononitrate extended release tablets 60 mg dose. The administration of extended release tablet 120 mg (2 ´ 60 mg tablets every 24 hours for 7 days) produced a dose-proportional increase in C_max and AUC, without changes in T_max or the terminal half-life. The older group (65-74 years) showed 30% lower apparent oral clearance (CI/F) following the higher dose, ie, 120 mg, compared to the younger group (45-64 years); CI/F was not different between the two groups following the 60 mg regimen. While CI/F was independent of dose in the younger group, the older group showed slightly lower CI/F following the 120 mg regimen compared to the 60 mg regimen. Differences between the two age groups, however, were not statistically significant. In the same study, females showed a slight (15%) reduction in clearance when the dose was increased. Females showed higher AUCs and C_max compared to males, but these differences were accounted for by differences in body weight between the two groups. When the data were analyzed using age as a variable, the results indicated that there were no significant differences in any of the pharmacokinetic variables of isosorbide mononitrate between older (³65 years) and younger individuals (45-64 years). The results of this study, however, should be viewed with caution due to the small numbers of subjects in each age subgroup and consequently the lack of sufficient statistical power.

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