Drug Metabolism Synthetic (Phase II) Reactions

ALAN TALEVI; CAROLINA L. BELLERA

The ADME Encyclopedia. A Comprehensive Guide on Biopharmacy and Pharmacokinetics

Springer Nature

Año: 2022; p. 394 - 400

In synthetic (or Phase II or conjugation) reactions, an endogenous or exogenous compound (the substrate of the reaction) is coupled to an endogenous conjugating moiety (sometimes called endocon). The conjugating moiety is usually polar and in the range of 100 to 300 Da (there are exceptions to this, though). The endocon is in general supplied by a cofactor (a coenzyme or co-substrate) where a high-energy chemical bond links the cofactor to the endocon. Synthetic reactions are almost always catalyzed by transferases [1]. The Phase II denomination comes from Williams? classic nomenclature and can be misleading, as it reflects the notion 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 that yields a secondary (or second-generation) metabolite. Functionalization (Phase I) reactions often precede conjugation reactions, since they introduce or expose a functional group that acts as a chemical ?anchor? site for the endocon. Accordingly, Phase I reactions may ?prepare? the substrate to undergo a Phase II reaction. However, there are too many deviations from this too general scheme. For instance, Phase I metabolites are sometimes excreted without experiencing a Phase II reaction. Similarly, the intact drug may directly undergo a Phase II transformation without a previous Phase I reaction (whenever the substrate already presents an accessible anchor site for the endocon). Moreover, a drug may undergo several subsequent Phase I reactions before being conjugated