ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 5. Metabolism and Bioactivity

Abstract

The Part 5 of our biochemical introduction to drug metabolism presents the pharmacological and toxicological consequences of drug and xenobiotic metabolism. As we have already shown [1 -5] and discuss here with specific focus, the consequences of the biotransformation of foreign compounds explain to a large extent the immense significance this discipline has acquired. When it comes to drug metabolism, its consequences are of utmost relevance in fields such as drug discovery and development, clinical pharmacology and toxicology, and therapeutics. The same relevance is now recognized to xenobiotic metabolism in, e.g., agrochemistry and food chemistry, industrial hygiene, workplace safety, and environmental welfare.Presenting the pharmacological and toxicological consequences of drug and xenobiotic metabolism can be achieved by focusing on rules and general principles, with a high risk of remaining abstract and failing to impress readers. Or it can be done with examples only, with the consequence that readers will remember fragmental data which may not help them to generalize and reason by analogy. The didactic approach followed here is simply the middle course, whereby we start with principles and illustrate them with examples, while, at other occasions, discussing illustrative cases from which principles are then derived.

Homology modeling and metabolism prediction of human carboxylesterase-2 using docking analyses by GriDock: a parallelized tool based on AutoDock 4.0

“…Apart from our previous studies focused on hCES1 [15,16], the hydrolyzing activity of the human hydrolases has been scantly analyzed in silico [17], although they play key roles in the hydrolytic metabolism of xenobiotics as well as in the activation of most carrierlinked prodrugs [18][19][20][21].…”

Quantitative monitoring of tamoxifen in human plasma extended to 40 metabolites using liquid-chromatography high-resolution mass spectrometry: new investigation capabilities for clinical pharmacology

“…The mechanisms of toxicity of a drug and its metabolites are diverse and can be (i) on-target, (ii) off-target with the binding of the drug/metabolites to an alternate target, or (iii) related to the covalent binding of reactive metabolites to proteins, nucleic acids, or membranes [7][8][9]. Strong side effects can also be observed with very low levels of metabolites or at a very low frequency (<1 case in 1,000 patients).…”

Role of PhaseIMetabolism in Drug Activation and Clinical Treatment Outcomes

“…Basically, there are two types of interactions between bioactive compounds and biological systems [6,11]. A drug acting on a biological system elicits a pharmacological and/or a toxic response, in other words a pharmacodynamic (PD) event.…”

“…To open this chapter, we note that the continuously increasing significance of drug metabolism investigations in drug discovery and development cannot be fortuitous [1][2][3][4][5][6][7][8][9]. The pharmacological and toxicological consequences of drug metabolism account for this phenomenon, which simultaneously drives, and is driven by, the many methodological, factual, and conceptual advances in this discipline.…”