Introductory Remarks on the Development of Isosorbide-5-Mononitrate

Abstract

The development of IS-5-MN as a useful drug for the prophylactic treatment of angina pectoris appears to be the final outcome of a wrong conclusion made 12 years ago. At that time and on several occasions later, Needleman et al. [9] claimed that orally administered organic nitrates were inactive due to their complete metabolic inactivation during their first passage through the liver. This provocative thesis stimulated interest in both the pharmacokinetics and pharmacodynamics of the metabolites produced. In the case of ISDN, it was already known from experiments in dogs that IS-5-MN is the main metabolite present in plasma [10], and this was later shown to apply to man, too [6]. At the same time, Wendt [15] as well as Bogaert and Rosseel [5] were able to demonstrate in isolated organs that the two mononitrates of isosorbide exhibit a definite nitrate-typical vascular activity, although it was less than that of the parent compound. Stauch et al. [12] and Michel [8] were then the first to show antianginal activity after injection i.v. or into the pulmonary artery of coronary patients.