Comparative pharmacokinetics of isosorbide nitrates after repeated doses of sustained release isosorbide dinitrate

The plasma kinetics of isosorbide dinitrate (ISDN), isosorbide-5-nitrate (IS-5-N) and isosorbide-2-nitrate (IS-2-N) were investigated in 20 healthy male and female volunteers, after b.i.d. administration over 2 days of sustained release ISDN 20 mg and 40 mg capsules (Iso Mack Retard 20 mg and 40 mg) and of a 40 mg sustained release ISDN tablet as reference formulation. The means of the individual maximum ISDN concentrations during the complete 2-day treatment amounted to 10.4 ng/ml after the 40 mg capsule, 5.3 ng/ml after the 20 mg capsule and 5.3 ng/ml after the reference tablet. The corresponding figures of the metabolically generated IS-5-N were 355.5 ng/ml, 168.8 ng/ml and 161.5 ng/ml, respectively. The measured amounts of IS-5-N are expected to contribute to the overall antianginal effect of at least the 40 mg capsule. According to the b.i.d. schedule, ISDN and the two mononitrates accumulated in the plasma after all three tested formulations. However, during the treatment with the 20 mg and the 40 mg capsules, accumulation was practically completed at the second day, while it was found to be more extended during treatment with the reference product. In terms of areas under the curve, the mean bioavailability of the 40 mg sustained release capsule relative to the reference formulation was 198% with respect to ISDN, and 197% both with respect to IS-2-N and IS-5-N. On the other hand, perfect dose-linearity of all relevant pharmacokinetic parameters of all three measured isosorbide nitrates was observed for the 20 mg and the 40 mg dose of the capsule.(ABSTRACT TRUNCATED AT 250 WORDS)