Oral absorption and disposition of isosorbide dinitrate and isosorbide mononitrates in man

Abstract

The plasma concentrations of isosorbide dinitrate (ISDN) and its two pharmacologically active metabolites isosorbide 2-mononitrate (IS-2-MN) and isosorbide 5-mononitrate (IS-5-MN) were determined after oral administration of 20 mg ISDN and 20 mg of each of the mononitrates. The mean concentration-time curve of ISDN showed a peak of 51.6 ng/ml 15 min after drug intake, and declined bi-exponentially with a terminal half-life of 36.5 min. The mean concentrations of the simultaneously measured metabolic products IS-2-MN and IS-5-MN reached a maximum of 40.5 ng/ml and 144.4 ng/ml, respectively. In contrast, after the direct ingestion of isosorbide mononitrates, peaks of 409.1 ng/ml (IS-2-MN) and 483.2 ng/ml (IS-5-MN) were observed in the corresponding mean curves. Mean half-lives of 1.72 h for IS-2-MN and 4.20 h for IS-5-MN were calculated. The mean apparent volumes of distribution were 44.5 l (IS-2-MN) and 34.4 l (IS-5-MN), suggesting that the isosorbide mononitrates are distributed throughout the whole body fluid. After ISDN administration, it was estimated that 3.0 mg IS-2-MN and 7.8 mg IS-5-MN reached the systemic circulation. This corresponds to 63% of the ISDN dose being converted to isosorbide mononitrates by metabolic processes.