Metabolism of nomifensine to a dihydroisoquinolinium ion metabolite by human myeloperoxidase, hemoglobin, monoamine oxidase A, and cytochrome P450 enzymes.
Nomifensine is an antidepressant agent that was removed from use because of a high incidence of hemolytic anemia. It contains an N-methyl-8-aminotetrahydroisoquinoline ring which has the potential to be oxidized to quaternary dihydroisoquinolinium and isoquinolinium ions, albeit such a transformation had not been previously observed. In this report, we demonstrate the conversion of nomifensine to a dihydroisoquinolinium ion metabolite by several human enzymes. Human liver microsomes supplemented with NADPH generated the dihydroisoquinolinium ion metabolite along with other hydroxylated metabolites, whereas when supplemented with t-butyl peroxide, only the dihydroisoquinolinium ion metabolite was observed. Monoamine oxidase A, but not monoamine oxidase B, catalyzed this reaction, as well as human hemoglobin supplemented with H2O2. Human myeloperoxidase catalyzed this reaction in the presence of H2O2, and activation of the reaction was observed when incubations were conducted in the presence of acetaminophen at concentrations relevant to those measured in humans. The reaction was also observed in human whole blood. The equilibrium between the dihydroisoquinolinium ion and carbinolamine was shown to have a pK of about 11.7. The dihydroisoquinolinium ion was shown to react with cyanide and borohydride, but not glutathione. These findings suggest that the electrophilic nomifensine dihydroisoquinolinium metabolite, which can be generated by several enzymes, could be behind toxic responses to nomifensine such as hemolytic anemia and hepatotoxicity.
Obach
R Scott
RS
Department of Pharmacokinetics, Dynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA. r.scott.obach@pfizer.com
Dalvie
Deepak K
DK