Isosorbide dinitrate bioavailability, kinetics, and metabolism

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Abstract
The kinetics of isosorbide dinitrate (ISDN) after a dose of 5 mg i.v. and the bioavailability of a sublingual and an oral preparation of ISDN were studied. Plasma levels of isosorbide 5-mononitrate (IS-5-MN), isosorbide 2-mononitrate (IS-2-MN) and ISDN were determined by gas liquid chromotography. After i.v. and sublingual dosing, ISDN plasma levels declined biexponentially and were adequately described by an open 2-compartment body model. Distribution was rapid; that t1/2 was 4.7 min after i.v. injection and 8.7 min after sublingual dosing. The volume of distribution at steady state was 90 l. The terminal disappearance t1/2 was 54.7 min after i.v. injection, 48.8 min after sublingual dosing and 47.7 min after oral dosing. Total plasma clearance was 136 l/h, 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 1st-pass effect was not avoided by sublingual ISDN dosing. After i.v. ISDN, mononitrate plasma levels were adequately described by another 2-compartment body model. The terminal t1/2 was 4.33 h for IS-5-MN and 1.83 h for IS-2-MN. Noncompartmental calculations of the mononitrate levels revealed 100% systemic availability after oral and sublingual ISDN. ISDN was completely absorbed from the gastrointestinal tract, but 70% was metabolized during the 1st pass through the liver. After 5 mg i.v. ISDN, 16 .mu.mol IS-5-MN and 5.3 .mu.mol IS-2-MN reached systemic circulation. The entire dose of ISDN was converted to its 2 metabolites in a ratio of 3:1.