Chronopharmacology of oral nitrates in healthy subjects

The pharmacokinetics and the hemodynamic effects (blood pressure, heart rate) of oral organic nitrates have been investigated in healthy subjects after oral single-dose application either in the morning or in the evening. Isosorbide-5-monitrate (IS-5-MN, 60 mg) was administered as an immediate-release tablet or as a slow-release formulation. Isosorbide dinitrate (ISDN, 20 mg) was ingested as an immediate-release tablet. After administration of IS-5-MN as an immediate-release tablet, the drug was more rapidly absorbed in the morning (tmax of 0.9 h) than in the evening (tmax of 2.1 h). The rapid absorption led to more pronounced effects in the morning, at which time maximum drug concentrations occurred at the same time as peak effects were observed. After evening administration, however, peak effects were in advance of the maximum drug concentrations. No chronokinetics were observed after application of the slow-release formulation of IS-5-MN. In accordance with the results of the immediate-release formulation, peak effects of the slow-release preparation occurred significantly earlier than peak drug concentrations after evening than after morning dosing. ISDN bioavailability was higher after morning than after evening administration and hemodynamic effects were more pronounced in the evening than in the morning. These results show that daily variations in pharmacokinetics and/or hemodynamic effects can be observed with oral nitrates. In addition, galenic formulation can influence the time-specified pharmacokinetics of IS-5-MN.