Cross-enzyme inhibition by gabexate mesylate: Formulation and reactivity study

Gabexate mesylate (GM; commercialized under the brand name FOY®) is a non antigenic synthetic inhibitor of plasmatic and pancreatic serine proteinases, that is used therapeutically in the treatment of pancreatitis and disseminated intravascular coagulation, and as a regional anticoagulant for hemodialysis. The inhibitory effect of GM on nitric oxide synthase as well as serine proteinases and swine kidney copper amine oxidase, all acting on cationic substrates, has been investigated. On the basis of the available X-ray crystal structures of the enzymes considered, the possible binding mode(s) of GM has been analyzed. The enzyme cross-inhibition by GM suggests that the use of this drug should be under careful control. With the aim to improve the scarce plasma stability of GM, the positively charged drug has been complexed to the surface of preformed anionic liposomes. The liposome-complexed GM half-life increases by about 5 fold, indicating the protective effect of liposomes on GM degradation. Moreover, the GM complexation with liposomes does not alter its inhibitory activity on NOS-I and porcine pancreatic trypsin.