[55] Cytochrome P450 metabolic intermediate complexes from macrolide antibiotics and related compounds

This chapter discusses the cytochrome P450 metabolic intermediate (MI) complexes from macrolide antibiotics and related compounds. Some MI generated by oxidative metabolism of certain compounds can bind to the heme of the P450 by which they were formed to form a stable ferrous heme complex. The “intermediate” notation derives from the inability, in most cases, to regenerate the complex once it has been dissociated by oxidation and the apparent inability of intermediates to move and bind to adjacent ferrous P450 that did not form them. Although the first such complexes were generated from methylenedioxybenzene derivatives, the ability of a wide range of pharmacologically active amine drugs to form MI complexes has generated widespread interest, eventually resulting in the observation of their formation from macrolide antibiotics. Thus, macrolides that form a MI complex possess an amino sugar, usually present as a tertiary amine, which after oxidative demethylation can be further oxidized to a nitroso intermediate.