Extension of the blood half-life of glyceryl trinitrate: Inhibition of glutathione organic nitrate ester reductase activity in the rat and guinea pig

Abstract

Cephalothin, penicillin G and probenecid inhibited GSH organic nitrate ester reductase (ONER) and several other enzymatic activities of GSH- S-transferases (EC 2.5.1.18) from rat and guinea pig liver. Erythrityl tetranitrate, a substrate for ONER, inhibited the aryl and alkyl transferase activities of two guinea pig liver GSH- S-transferases. These findings support the concept that ONER is one of the several activities possessed by the GSH- S-transferases. In an examination of possible in vivo action, parenteral administration of these inhibitors 2–30 min prior to i.v. administration of [ 14C]glyceryl trinitrate resulted in a 50–100 per cent increase in the half-time of the metabolism phase of [ 14C]glyceryl trinitrate clearance from the blood and postponed the appearance of metabolites. This presumably occurs through the in vivo inhibition of GSH-ONER activity of the GSH- S-transferases and suggests a possible means of prolonging the pharmacologie action of nitrate esters.