Absorption
Isosorbide dinitrate is readily (and almost completely) absorbed from the GI tract and oral mucosa, but considerable variations in the bioavailability of the drug (10-90%) have been reported as a result of extensive first-pass metabolism in the liver. The bioavailability of isosorbide dinitrate, as unchanged drug, following oral administration of conventional tablets (25%) generally appears to be about half that following sublingual administration (40-50%); however, in one study, systemic bioavailability of the drug was similar (about 29%) for both oral conventional tablets and sublingual tablets. It has been suggested that the reduced bioavailability of sublingual tablets of isosorbide dinitrate may result from swallowing a portion of the drug dissolved from such tablets, possibly because absorption of the drug is slow relative to the time that a sublingual dose might reasonably be retained in the mouth. Although multiple-dose studies of isosorbide dinitrate sublingual tablets have not been conducted, multiple-dose studies of isosorbide dinitrate oral conventional tablets indicate that progressive increases in bioavailability may occur during chronic therapy.
Although some evidence suggests that systemic bioavailability of isosorbide dinitrate from extended-release oral tablets is similar but slightly less than that from conventional oral tablets, other evidence suggests that considerable variability exists for various extended-release preparations and that some preparations may be substantially less bioavailable than conventional tablets. Because pharmacologic effects of the drug also depend on serum concentrations of active metabolites (e.g., isosorbide-5-mononitrate, isosorbide-2-mononitrate), comparisons should extend beyond systemic bioavailability of unchanged drug alone. Unfortunately, many studies do not specify or provide incomplete data on these metabolites. In addition, although most studies have employed single doses, the pharmacokinetics and/or bioavailability of the drug may be affected substantially during multiple dosing because the metabolites may decrease the metabolic clearance of isosorbide dinitrate; therefore, predictions based on single-dose studies are uncertain.
Although food may decrease substantially mean peak plasma concentrations of isosorbide dinitrate, total bioavailability of the drug does not seem to be affected.
Considerable interindividual variations (approximately 5- to 11-fold) in peak plasma concentrations attained have been reported with a specific oral dose of isosorbide dinitrate. Following administration of isosorbide dinitrate as sublingual or conventional oral tablets, peak plasma isosorbide dinitrate concentrations are reached in 10-15 or 60 minutes, respectively. Elevated blood concentrations of isosorbide dinitrate have been observed in patients with cirrhosis.
Isosorbide mononitrate also is readily absorbed from the GI tract. Because isosorbide mononitrate, unlike isosorbide dinitrate, does not undergo first-pass hepatic metabolism, the bioavailability of isosorbide mononitrate conventional or extended-release tablets is approximately 100 or 77-80%, respectively.
In general, food was found to delay the rate but not the extent of absorption (less than 10%) of conventional or extended-release isosorbide mononitrate tablets. Following oral administration of conventional or extended-release isosorbide mononitrate tablets, peak plasma concentrations of isosorbide mononitrate are achieved within 0.5-1 or about 3-4.5 hours, respectively. In one study, following oral administration of a 40-mg conventional isosorbide mononitrate tablet in fasted healthy individuals, mean peak plasma concentrations of about 930 ng/mL were achieved within about 1 hour. In addition, in another study, following oral administration of a 60- or 120-mg extended-release tablet of isosorbide mononitrate in healthy individuals, peak plasma concentrations of about 557 or 1151 ng/mL were achieved within about 3 hours, respectively.
Following oral administration of a single 40-mg dose of isosorbide dinitrate given in fixed combination with 75 mg of hydralazine hydrochloride (2 tablets of BiDil) in a limited number of healthy adults, peak plasma isosorbide concentrations of 76 ng/mL per 65 kg were reached in 1 hour. The effect of food on the bioavailability of isosorbide dinitrate when administered in fixed combination with hydralazine hydrochloride is not known.
Although optimal therapeutic plasma concentrations have not been determined, it has been suggested that the therapeutic plasma concentration of isosorbide mononitrate (both for the management of angina and heart failure) is 100 ng/mL. In addition, evidence from clinical studies of isosorbide dinitrate and isosorbide mononitrate have shown that dosing regimens that result in plasma isosorbide mononitrate concentrations that fall below 100 ng/L prior to the administration of the next dose may be associated with a lower risk of developing tolerance.
The approximate onset and duration of action of various dosage forms of isosorbide dinitrate (ISDN) and isosorbide mononitrate (ISMN) are shown in Table 1 and Table 2.
| sublingual ISDN |
within 3 min |
2 h |
| chewable ISDN |
within 3 min |
2-2.5 h |
| oral ISDN |
1 h |
up to 8 h |
| oral ISMN |
1 h |
5-7 h |
| extended-release ISDN |
1 h |
8 h |
| extended-release ISMN |
1 h |
12 h |
| sublingual ISDN |
within 15-30 min |
1.5-4 h |
| chewable ISDN |
5 min |
2-3 h |
| oral ISDN |
within 20-60 min |
4-6 h |
| oral ISMN |
10-30 min |
at least 6 h |
| extended-release ISDN |
within 2 h |
up to 12 h |
| extended-release ISMN |
20-30 min |
at least 6 h |
The onset and duration of action following intrabuccal administration are probably similar to those after sublingual administration of isosorbide dinitrate; however, no studies are available.
