Principles of Drug Metabolism

Abstract

The focus of this chapter is mainly on drug metabolism reactions and connected information of significance to medicinal chemists. The types, selectivities, and consequences of drug metabolism are presented in the introduction. Oxidoreductases are discussed in the next section, together with a systematic and extensive treatment of the chemical groups they target and the functionalization reactions they catalyze. Particular attention is paid to cytochromes P450 and their multiplicity, specificities, and relative importance. Section 3 is dedicated to the transferases and the conjugation reactions they catalyze, e.g., glucuronidation and glutathione conjugation. The various biological factors influencing drug metabolism are examined in Section 4. These are subdivided into interindividual factors (that depend on the genome) and intraindividual factors (that can vary with time or because of external influences). The last section, which is particularly close to the interests of medicinal chemists, discusses structure‐metabolism relationships, prodrug design, and toxophoric groups.

Synthesis and Cytotoxic Profile of 3,4-Methylenedioxymethamphetamine (“Ecstasy”) and Its Metabolites on Undifferentiated PC12 Cells: A Putative Structure−Toxicity Relationship

“…The research on the biotransformation reactions of xenobiotics, which play a major role in influencing the nature, intensity, and duration of wanted and unwanted effects, is an important task in the medicinal chemistry field (7). A majority of the investigation has been based on the overall effects induced by the use of the drug, but little attention has been given to the putative activities of the metabolites themselves.…”

Musings on ADME Predictions and Structure-Activity Relations

“…To illustrate this point, just consider the low and overlapping substrate specificities of the major human cytochromes P450 (Table 3), whose physiological function is to oxidize xenobiotics to detoxify them and facilitate their subsequent excretion [10]. Another case in point is alpha-1 acid glycoprotein (AAG), a plasma macromolecule which binds and transports numerous drugs, but whose physiological functions remain incompletely understood.…”