N-Oxide Formation and Related Reactions in Drug Metabolism

Abstract

1. Tertiary amine drugs are converted into dealkylated and N-oxide metabolites by liver microsomal enzymes. The two reactions are catalyzed by NADPH-dependent microsomal electron transfer chains; the first involving NADPH-cytochrome c reductase and cytochrome P-450, the latter a different flavo-protein and no cytochrome P-450. The individual rates are highly dependent on the animal species and experimental conditions. 2. N-oxides can be further metabolized by dealkylation and/or by reduction. However, N-oxides are not obligatory intermediates in the dealkylation of tertiary amines. Rather, two alternative pathways are open to these compounds: C-oxygenation and N-oxygenation. 3. With imipramine and imipramine-N-oxide as substrates it could be shown that tertiary amine dealkylation and N-oxidation are catalyzed by microsomal enzymes only, whereas N-oxide dealkylation and reduction occur only in extra-microsomal compartments. With isotope trapping experiments the simultaneous occurrence of all four reactions could be demonstrated in NADPH-fortified liver homogenate, and the individual reaction rates could be determined. Experiments with liver slices, perfused livers and whole animals suggest a similar kinetic situation whereby N-oxide formation may well be a major pathway.