Drugs & Updates

How do drugs work in the body?

Overview

The metabolic breakdown of pharmaceuticals by living organisms, typically mediated by specialised enzyme systems, is known as drug metabolism. More specifically, xenobiotic metabolism refers to the set of metabolic pathways that change the chemical structure of xenobiotics, which are substances foreign to an organism’s normal biochemistry, such as any drug or poison. The term comes from the Greek words Xenos, meaning “stranger,” and biotic, meaning “related to living beings.” These biotransformational routes, which are found in all significant groupings of species, are thought to have existed long ago. These processes frequently detoxify harmful substances (although in some cases the intermediates in xenobiotic metabolism can themselves cause toxic effects). The field of pharmacokinetics investigates how drugs are metabolised.

An essential component of pharmacology and medicine is the metabolism of pharmacological medicines. For instance, a drug’s pharmacologic action’s duration and potency are determined by its rate of metabolism. Infectious disease multidrug resistance and cancer treatment are both impacted by drug metabolism, and dangerous drug interactions are frequently caused by the actions of some medications as substrates or inhibitors of enzymes involved in xenobiotic metabolism. The xenobiotic metabolism of microorganisms determines whether a pollutant will be broken down during bioremediation or persist in the environment, making these pathways crucial in environmental science. In agriculture, the xenobiotic metabolism enzymes, in particular the glutathione S-transferases, are crucial because they may result in pesticide and herbicide resistance.

Three steps make up drug metabolism. In phase I, xenobiotics are given reactive or polar groups by enzymes such as cytochrome P450 oxidases. In phase II processes, these changed molecules are then conjugated into polar compounds. Transferase enzymes, such as glutathione S-transferases, catalyse these processes. The conjugated xenobiotics may then undergo additional processing in phase III before being recognised by efflux transporters and expelled from cells. Drug metabolism frequently transforms lipophilic substances into hydrophilic byproducts, which are eliminated more quickly.

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Permeability barriers and detoxification

One of the main characteristics of xenobiotic toxic stress is the highly unpredictable nature of the precise substances to which an organism is exposed. The greatest hurdle that xenobiotic detoxification systems must overcome is their need to be able to eliminate the virtually infinite amount of xenobiotic molecules from the complex concoction of chemicals that make up normal metabolism. Physical barriers and low-specificity enzymatic systems are an elegantly combined approach that has evolved to overcome this limitation.

Cell membranes serve as hydrophobic permeability barriers for all organisms to regulate access to their internal environment. Polar chemicals cannot diffuse through these cell membranes, and transport proteins that specifically choose substrates from the extracellular environment mediate the uptake of beneficial substances. Because they are not recognised by any particular transporters, the majority of hydrophilic molecules cannot enter cells as a result of this selective uptake. Contrarily, hydrophobic substances cannot be controlled in their diffusion through these barriers, and as a result, organisms cannot use membrane barriers to exclude lipid-soluble xenobiotics.

However, the presence of a permeability barrier enables the evolution of detoxification mechanisms that take advantage of the hydrophobicity shared by membrane-permeable xenobiotics. As a result, these systems circumvent the specificity issue by metabolising practically any non-polar molecule due to their broad substrate specificities. Because they are polar and typically include one or more charged groups, useful metabolites are omitted.

The mechanisms described above are unable to detoxify the reactive by-products of normal metabolism since these species are formed from regular cellular components and frequently exhibit their polar properties. However, because there are so few of these molecules, particular enzymes can identify and eliminate them. The glyoxalase system, which eliminates the reactive aldehyde methylglyoxal, and the numerous antioxidant systems, which get rid of reactive oxygen species, are two examples of these particular detoxification systems.

References

1.    https://pubmed.ncbi.nlm.nih.gov/9129943/

2.    https://pubmed.ncbi.nlm.nih.gov/2198020/

Author

 Yash Batra

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