Plasma isosorbide dinitrate concentrations and effect after chewable and high-dose, sustained-release formulations

Area of Science:

• Pharmacology
• Clinical Pharmacy

Background:

• Isosorbide dinitrate (ISDN) is a vasodilator used for angina.
• Understanding its bioavailability and tolerance is crucial for effective dosing.

Purpose of the Study:

• To compare the bioavailability of chewable ISDN with a slow-release formulation.
• To investigate the development of tolerance to ISDN's effects over time.

Main Methods:

• Eight healthy volunteers received either 5 mg chewable ISDN hourly or 40 mg slow-release ISDN every 8 hours.
• Plasma concentrations of ISDN and metabolites were measured.
• Digital plethysmography (DPG) assessed ISDN's vasodilatory effects.

Main Results:

• Mean steady-state plasma concentrations (Cpss) were similar between the two formulations.
• The relative bioavailability of the slow-release formulation was 111%.
• DPG showed similar effects initially, but a 30% decrease in effect after 48 hours indicated tolerance.

Conclusions:

• Buccal absorption of ISDN provides comparable bioavailability to sustained-release preparations.
• Tolerance to ISDN develops with prolonged use, likely due to physiological counter-regulation.
• DPG is suitable for assessing short-term ISDN bioavailability but not for long-term steady-state evaluations due to tolerance.