Isosorbide dinitrate kinetics and dynamics after intravenous, sublingual, and percutaneous dosing in angina

Abstract

Isosorbide dinitrate (ISDN) kinetics and dynamics were examined after various routes of administration for angina. Given intravenously, ISDN kinetics were apparently linear over the range of infusion rate (0.083 and 0.133 mg/min) and duration (15 min and 1 and 2 hr) studied. Mean +/- SD systemic clearance of ISDN was 3.4 +/- 1.4 l/min and volume of distribution (VdSS or Vdarea) about 100 l. These data are consistent with the presence of extensive extrahepatic metabolism. In six patients, sublingual ISDN (5 mg) was also given and mean bioavailability of 59% (19% to 93%) for this route was determined. For this group, sublingual absorption of intact ISDN was incomplete and variable. The presence of a longer disappearance t 1/2 after sublingual dosing suggested that the input process may be rate limiting. After percutaneous application of a topical formulation (100 mg over an area of 400 cm2), steady-state plasma concentrations at about 7 ng/ml were maintained from 6 to 24 hr. The bioavailability of the topical application was estimated at 30%. At the doses given, intravenous ISDN had no apparent effect on heart rate but induced significant reduction in standing systolic blood pressure. The effect vs the ISDN concentration profile was described by a hysteresis loop, indicating that changes in blood pressure response lag behind changes in plasma ISDN concentration. After intravenous dosing, peak plasma ISDN concentration and peak effect (maximum change in standing systolic blood pressure). At the doses used, both sublingual and percutaneous ISDN induced less distinct circulatory changes than the intravenous infusion.

Understanding the Hysteresis Loop Conundrum in Pharmacokinetic / Pharmacodynamic Relationships

“…It was observed that the changes in standing systolic pressure were greater during the declining phase than in the ascending phase after IV and sublingual administration [44], this correlated with previous studies after oral administration [108]. …”

“…The organic nitrate isosorbide dinitrate (ISDN) exhibited counter-clockwise hysteresis after intravenous infusion (0.133 mg/min for 15 min) or sublingual (5 mg) administration (Figure 5) [44]. It was observed that the changes in standing systolic pressure were greater during the declining phase than in the ascending phase after IV and sublingual administration [44], this correlated with previous studies after oral administration [108].…”

Relationship of Pharmacokinetic and Pharmacodynamic Properties of the Organic Nitrates

“…After a single sublingual isosorbide dinitrate dose a counterclockwise hysteresis of the plasma concentration-effect relationship exists; i.e., a greater effect is observed at the same plasma isosorbide dinitrate concentration (Morrison et al 1983) which influences data interpretation. The metabolites may also reduce denitration of isosorbide dinitrate in the vessel wall (Fung 1985).…”

“…The mean elimination half-life of isosorbide dinitrate is approximately 1 hour, but may vary from 35 to 120 minutes. However, after long term dosing, a much longer terminal phase tl;' of 7.7 ± 2.6 hours was reported, as a result of accumulation of metabolite isosorbide-5-mononitrate, which reduces hepatic isosorbide dinitrate extraction (Morrison et al 1983).…”

“…Sustainedrelease preparations have reduced bioavailability secondary to incomplete absorption. Mean bioavailability of a sublingual formulation has varied from 31 to 59%, with peak concentration occurring by 30 minutes (Bogaert 1983;Fung 1985;Morrison et al 1983). Following topical administration, bioavailability has ranged from 10 to 30% (Morrison et al 1983).…”