Drug metabolism and disposition: the biological fate of chemicals

A pharmacokinetic model for isosorbidedinitrate, isosorbide-2-mononitrate, and isosorbide-5-mononitrate.

PMID 1976063


A pharmacokinetic model is proposed to describe the plasma levels of isosorbidedinitrate (ISDN) and its two pharmacologically active metabolites, isosorbide-2-mononitrate (IS-2MN) and isosorbide-5-mononitrate (IS-5MN), following the oral administration of several 20-mg sustained release formulations of ISDN. Absorption of ISDN from the gastrointestinal tract appears first-order. A three compartment model is used to describe ISDN systemic plasma levels with t1/2 alpha = 7 min, t1/2 beta = 48 min and t1/2 gamma = 7.5 hr. The long t1/2 gamma is due to the slow release of ISDN from a peripheral compartment. ISDN undergoes extensive first-pass hepatic metabolism to IS-2MN and IS-5MN. The metabolic pathways appear to be close to saturation at an ISDN dose of 20 mg. Both IS-2MN and IS-5MN systemic plasma levels can be described by one compartment models with first-order elimination (respective elimination half-lives are 1.9 and 5.1 hr). The central compartment volumes of distribution for ISDN, IS-2MN and IS-5MN (116, 57, and 38 liters, respectively) are in agreement with reported literature values. This model is of particular usefulness as a formulation tool in designing sustained release ISDN formulations of the type investigated here since the observed first-order absorption rate constant correlates well with the in vitro first-order dissolution rate constant. Therefore, for these formulations, plasma levels can be simulated using data generated from in vitro dissolution studies, thus obviating the need for multiple human bioavailability studies.

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I0775020 Isosorbide 2-nitrate, European Pharmacopoeia (EP) Reference Standard