Metabolism of procainamide in the perfused rat liver.

We have previously produced evidence that procainamide forms a reactive metabolite. This study of the metabolism of procainamide in a perfused rat liver was aimed at providing clues to the identity of this reactive metabolite. Several metabolites were found that had not been previously described and three of these were identified. Probably the most significant of these metabolites is the phenol, N-acetyl-3-hydroxyprocainamide. This phenol could have been formed from either a hydroxylamine or an arene oxide intermediate and either of these could represent a reactive metabolite. In contrast to the metabolism of procainamide, the phenol metabolite, N-acetyl-3-hydroxyprocainamide, is not formed in significant quantities from N-acetylprocainamide. This implies that oxidation of procainamide to 3-hydroxyprocainamide precedes acetylation to give N-acetyl-3-hydroxyprocainamide. As N-acetylation of procainamide decreases both its toxicity and the formation of the oxidative phenol metabolite, among the hypotheses to be explored is relationship between the formation of the phenol metabolite and the toxicity of procainamide. The other metabolites that were identified were N-acetylprocainamide N-oxide and N-acetyl-4-aminohippuric acid.