Drug Metabolism Functionalization (Phase I) Reactions

Abstract

Functionalization (or Phase I) reactions of drug metabolism are those that introduce a functional drug to their substrates (for instance, in hydroxylation) or modify an existing one (e.g., in hydrolysis). The term functionalization is sometimes preferred to Williams’ classic Phase I denomination. Williams’ nomenclature reflects the usual scheme of sequential metabolism, where the parent drug is converted to a primary, or first-generation, metabolite, which in turn is subjected to a second biotransformation reaction that yields a secondary, or second-generation, metabolite. Whereas it is true that functionalization reactions often “prepare” their substrate to undergo a conjugation (Phase II) reaction (because they provide the substrate with a chemical “anchor” site for a conjugation to occur, such as a -OH or a -NH function), there are many deviations from this too general scheme. For instance, many Phase I metabolites are excreted without experiencing Phase II reactions. Similarly, the intact drug may directly undergo a Phase II transformation without a previous Phase I reaction. A drug may undergo one or more subsequent Phase I reactions before being conjugated (see Fig. 1 for figures). Finally, drug metabolism tends to operate in parallel and not only serially, since many different biotransformations occur simultaneously to different drug molecules of the same compound.