Drug metabolism

• Drug metabolism is a crucial process in the body that involves the conversion of medications and other foreign substances (xenobiotics) into metabolites, which are more easily excreted from the body.
• The primary site of drug metabolism is the liver, although other organs, such as the kidneys, intestines, lungs, and skin, also contribute to this process.
• Drug metabolism plays a significant role in determining the pharmacokinetics and efficacy of medications, as well as influencing the occurrence of drug interactions and potential adverse effects.

Xenobiotic metabolism

Phases of Drug Metabolism

• Drug metabolism occurs in two main phases:

Phase I Metabolism:

Phase I metabolism involves chemical modifications of the drug molecule, such as oxidation, reduction, and hydrolysis. The main objective of Phase I metabolism is to introduce or expose functional groups on the drug, making it more amenable to further modifications in Phase II.

Key reactions in Phase I metabolism include:

• Oxidation: The addition of oxygen or removal of hydrogen atoms from the drug molecule, catalyzed by enzymes known as cytochrome P450 (CYP) enzymes.
• Reduction: The addition of electrons to the drug molecule, usually performed by enzymes such as reductases.
• Hydrolysis: The cleavage of chemical bonds in the drug molecule using water, catalyzed by various hydrolytic enzymes.

Phase II Metabolism:

• Phase II metabolism involves the conjugation of the modified drug (from Phase I) with endogenous molecules to form water-soluble metabolites that are readily excreted in urine or bile.
• Conjugation typically involves attaching molecules, such as glucuronic acid, sulfate, or amino acids, to the drug or its Phase I metabolites.

Key reactions in Phase II metabolism include: Glucuronidation: Conjugation with glucuronic acid, catalyzed by enzymes called UDP-glucuronosyltransferases (UGTs). Sulfation: Conjugation with sulfate groups, catalyzed by sulfotransferases (SULTs). Acetylation: Conjugation with acetyl groups, catalyzed by N-acetyltransferases (NATs). Amino Acid Conjugation: Conjugation with amino acids, catalyzed by various amino acid transferases.

Factors Affecting Drug Metabolism

Several factors can influence drug metabolism and impact an individual's response to medications:

• Genetic Variations: Genetic polymorphisms in drug-metabolizing enzymes can result in differences in drug metabolism among individuals. Some individuals may be rapid metabolizers, while others may be slow metabolizers, affecting drug efficacy and potential toxicity.
• Age: Drug metabolism can change with age, with the very young and elderly often experiencing altered drug clearance rates.
• Liver Function: Impaired liver function due to liver diseases or conditions can significantly impact drug metabolism.
• Drug Interactions: Some medications can inhibit or induce drug-metabolizing enzymes, leading to altered drug metabolism and potential interactions.
• Nutritional Status: Certain nutrients and dietary factors can influence drug metabolism.
• Gender: Some drug-metabolizing enzymes may exhibit differences between males and females.

Clinical Significance of Drug Metabolism

Understanding drug metabolism is vital in clinical practice for several reasons:

• Drug Interactions: Drug metabolism can lead to significant drug interactions when medications affect the activity of drug-metabolizing enzymes.
• Pharmacokinetics: Drug metabolism plays a key role in determining the half-life and clearance of medications, which affects dosing regimens and therapeutic efficacy.
• Individualized Medicine: Knowledge of genetic polymorphisms in drug-metabolizing enzymes can help in individualizing drug therapy.
• Drug Toxicity: Some medications undergo metabolic activation to toxic intermediates, leading to potential adverse effects.
• Drug Design: Considering drug metabolism is essential in the design of medications with appropriate pharmacokinetic properties.
• Clinical Trials: Drug metabolism data are crucial in evaluating the safety and efficacy of new medications during clinical trials.

Conclusion

• Drug metabolism is a complex and essential process that influences the pharmacokinetics, efficacy, and safety of medications.
• Understanding the phases of drug metabolism, key enzymes involved, and factors affecting this process is crucial for healthcare professionals to optimize drug therapy, minimize drug interactions, and ensure patient safety and well-being.

See also

• Antioxidant
• Biodegradation
• Bioremediation
• Dose dumping
• Microbial biodegradation

References

• Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138(1):103-141. doi:10.1016/j.pharmthera.2012.12.007.
• Nebert DW, Russell DW. Clinical importance of the cytochromes P450. Lancet. 2002;360(9340):1155-1162. doi:10.1016/s0140-6736(02)11203-7.
• Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med. 2005;352(21):2211-2221. doi:10.1056/NEJMra032424.

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