Isosorbide dinitrate bioavailability, kinetics, and metabolism

Abstract

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 t1/2 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 t1/2 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 t1/2 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 mumol IS-5-MN and 5.3 mumol 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).