Isosorbide dinitrate bioavailability, kinetics, and metabolism

We studied the kinetics of isosorbide dinitrate (ISDN) after a dose of 5 mg iv and the bioavailability of a sublingual and an oral preparation of ISDN. Plasma levels of isosorbide 5‐mononitrate (IS‐5‐MN), isosorbide 2‐mononitrate (IS‐2‐MN), and ISDN were determined by GLC. After intravenous and sublingual dosing, ISDN plasma levels declined biexponentially and could adequately be described by an open two‐compartment body model. Distribution was rapid; the t ½ was 4.7 minutes after intravenous injection and 8.7 minutes after sublingual dosing. The volume of distribution at steady state was 90 L. The terminal disappearance t ½ was 54.7 minutes after intravenous injection, 48.8 minutes after sublingual dosing, and 47.7 minutes after oral dosing. Total plasma clearance was 136 L/hr, exceeding normal liver plasma flow and indicating extrahepatic metabolism of ISDN. ISDN bioavailability after oral (10 mg) or sublingual dosing (10 mg) was similar (about 29%), indicating that the first‐pass effect cannot be avoided by sublingual ISDN dosing. After intravenous ISDN, mononitrate plasma levels could be adequately described by another two‐compartment body model. The terminal t ½ was 4.33 hours for IS‐5‐MN and 1.83 hours for IS‐2‐MN. Noncompartmental calculations of the mononitrate levels revealed 100% systemic availability after oral and sublingual ISDN. We assume that ISDN was completely absorbed from the gastrointestinal tract, but 70% was metabolized during the first pass through the liver. After 5 mg iv ISDN, 16 µmol IS‐5‐MN and 5.3 µmol IS‐2‐MN reached systemic circulation. The entire dose of ISDN was converted to its two metabolites in a ratio of 3:1 (i.e., 75% IS‐5‐MN and 25% IS‐2‐MN). Clinical Pharmacology and Therapeutics (1985) 38, 140–149; doi: 10.1038/clpt.1985.150