This chapter was written with a number of objectives in mind. As a priority, it was felt necessary to demonstrate to medicinal chemists the fact that metabolic reactions of hydrolysis and conjugation are not second in importance to the redox reactions comprehensively surveyed in 5.05 Principles of drug metabolism 1: Redox reactions The variety of substrates and products presented here is just as ample as that discussed in 5.05 Principles of drug metabolism 1: Redox reactions, and the toxicological consequences (detoxification and toxification) of hydrolyses and conjugations are as important as those of redox reactions.

But differences do exist, and they may explain why hydrolyses and conjugations do not always receive the attention they deserve in drug discovery and development. First, numerous sites of potential enzymatic attack (think of Csp3 and Csp2 atoms) exist in substrates of oxidoreductases, most particularly in substrates of cytochrome P450 s. As a result, about 90% or more of candidates, drugs, and other xenobiotics are substrates of CYPs. In contrast, hydrolyses and conjugations need specific target groups whose occurrence is less frequent than that of the target groups of CYPs. As a result, each of the metabolic reactions discussed in this chapter knows fewer substrates than CYP-catalyzed monooxygenations.

But this comparatively limited number of xenobiotic substrates per metabolic reaction is compensated by two important facts. The first is the impressive variety of existing transferases and the variety of endocons they transfer. In other words, the chemical nature of the functional groups introduced into substrates by conjugation reactions is markedly more diverse than that resulting from redox reactions. And the second compensating factor is the fact that while CYPs do indeed recognize more substrates than transferases during phase I metabolism, a more balanced situation prevails when considering the further processing of metabolites, in other words secondary metabolic reactions. Indeed, CYP-catalyzed monooxygenations do create the target groups for glucuronidation and other conjugations, meaning that there is markedly more scope for conjugation during phase II metabolism, particularly in in vivo investigations.

In closing, it appears from the above that the many distinct functionalities that differentiate substrates from their products of hydrolysis or conjugation offer a constant challenge to the expertise and intuition of pharmacochemists, bioanalysts, pharmacokineticists, pharmacologists, and toxicologists. The ultimate objective of this chapter is to appeal by providing enough factual evidence and educate by presenting a structured conceptual scaffold.

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