Drug metabolism

Drug metabolism involves the biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems. This process is crucial for detoxifying xenobiotic substances, including drugs, facilitating their excretion from the body. The liver is the primary site for drug metabolism, utilizing mechanisms like oxidation, reduction, and conjugation. Factors affecting drug metabolism include genetics, age, and the health of the liver and kidneys. Historical research has significantly advanced our understanding of these metabolic pathways, highlighting the importance of cytochrome P450 enzymes in drug metabolism.

Detoxification Systems:

• Organisms face unpredictable exposure to various compounds.
• Detoxification systems must remove numerous xenobiotic compounds.
• Cell membranes act as hydrophobic barriers controlling internal access.
• Transport proteins mediate the uptake of useful molecules.
• Detoxification systems exploit hydrophobicity to metabolize non-polar compounds.
• Xenobiotic metabolism consists of modification, conjugation, and excretion.
• Phase I introduces reactive and polar groups into substrates.
• Cytochrome P-450-dependent oxidase system is common in phase I.
• Phase I reactions involve oxidation, reduction, and hydrolysis.
• Phase I can convert inactive compounds to active or toxic forms.
• Xenobiotic metabolites are conjugated with charged species like GSH, sulfate, glycine, or glucuronic acid.
• Conjugation reactions occur at carboxy, hydroxy, amino, and thiol groups on drugs.
• Glutathione S-transferases (GSTs) are crucial enzymes in this process.
• Detoxification of endogenous reactive metabolites requires specific recognition systems.
• Specific detoxification systems like the glyoxalase system and antioxidants handle these toxins.

Drug Metabolism Mechanisms:

• Cytochrome P450 monooxygenase system is involved in oxidation.
• Flavin-containing monooxygenase system contributes to oxidation.
• Alcohol dehydrogenase, aldehyde dehydrogenase, and monoamine oxidase play roles in oxidation.
• Co-oxidation by peroxidases is another oxidation mechanism.
• NADPH-cytochrome P450 reductase is involved in reduction.
• Reduction processes are essential in drug metabolism.
• Reduction reactions contribute to detoxification.
• Xenobiotic metabolites are conjugated with charged species in phase II reactions.
• Conjugation products have higher molecular weight and reduced activity compared to substrates.
• Enzymatic systems target endogenous toxins due to their similarity to useful metabolites.
• Different detoxification enzymes are needed for various endogenous toxins.

Sites of Drug Metabolism:

• The liver’s smooth endoplasmic reticulum is the primary site for drug metabolism.
• First-pass effect occurs when drugs are metabolized in the liver after absorption from the gut.
• Other drug metabolism sites include gastrointestinal epithelial cells, lungs, kidneys, and skin.
• Localized toxicity reactions often occur at these sites.

Factors Affecting Drug Metabolism:

• Cytochrome P450 monooxygenase system plays a crucial role in metabolizing lipophilic drugs.
• Enzyme induction increases metabolism rate, decreasing drug action duration and intensity.
• Physiological factors like age, genetics, and gut microbiota influence drug metabolism.
• Genetic polymorphism leads to variability in drug effects among individuals.
• Pathological conditions such as liver or kidney diseases can impact drug metabolism.

Historical Development and Research:

• Research on human detoxification processes began in the mid-nineteenth century.
• Basic detoxification reactions like methylation and acetylation were discovered in the nineteenth century.
• Enzymes and pathways responsible for metabolite production were investigated in the early twentieth century.
• Glutathione-transferases were identified in 1961, and cytochrome P450s in 1962.
• Modern biochemical research has elucidated the central role of these enzymes in xenobiotic metabolism.

Drug metabolism Data Sources