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Drug metabolism

Drug metabolism is the metabolismof drugs, their biochemicalmodification or degradation, usually through specialized enzymaticsystems. Drug metabolism often converts lipophilicchemical compoundsinto more readily excretedpolarproducts. Its rate is an important determinant of the duration and intensity of the pharmacological action of drugs.

Drugmetabolism can result in toxicationor detoxication- the activation or deactivation of the chemical. While both occur, the major metabolites of most drugs are detoxication products.

Drugs are almost all xenobiotics. Other commonly used organic chemicalsare also drugs, and are metabolized by the same enzymesas drugs. This provides the opportunity for drug-drug and drug-chemical interactionsor reactions.


  • 1 Phase I vs. Phase II
  • 2 Sites
  • 3 Major enzymes and pathways
    • 3.1 Phase I
      • 3.1.1 Oxidation
      • 3.1.2 Reduction
      • 3.1.3 Hydrolysis
    • 3.2 Phase II
  • 4 Factors that affect drug metabolism
  • 5 References

Phase I vs. Phase II

Phase I and Phase II reactions are biotransformationsof chemicals that occur during drug metabolism.

Phase I reactions usually precede Phase II, though not necessarily. During these reactions, polar bodies are either introduced or unmasked, which results in (more) polar metabolites of the original chemicals. Phase I reactions may occur by oxidation, reductionor hydrolysisreactions. If the metabolites of phase I reactions are sufficiently polar, they may be readily excreted at this point. However, many phase I products are not eliminated rapidly and undergo a subsequent reaction in which an endogenous substrate combines with the newly incorporated functional group to form a highly polar conjugate.

Phase II reactions — usually known as conjugation reactions — are usually detoxicationin nature, and involve the interactions of the polar functional groups of phase I metabolites.


Quantitatively, the liveris the principle organ of drug metabolism, although every biological tissuehas some ability to metabolize drugs. Factors responsible for the liver's contribution to drug metabolism include that it is a large organ, that it is the first organ perfused by chemicals absorbed in the gut, and that there are very high concentrations of most drug-metabolizing enzyme systems relative to other organs. If a drug is very readily and well-metabolized, it is said to show the first pass effect.

Other sites of drug metabolism include epithelial cellsof the gastrointestinal tract, lungs, kidneys, and the skin. These sites are usually responsible for localized toxicity reactions.

Major enzymes and pathways

Several major enzymes and pathways are involved in drug metabolism, and can be divided into Phase I and Phase II reactions:

Phase I


  • Cytochrome P450 monooxygenase system
  • Flavin-containing monooxygenase system
  • Alcohol dehydrogenaseand aldehyde dehydrogenase
  • Monoamine oxidase
  • Co-oxidation by peroxidases


  • NADPH-cytochrome P450 reductase
  • Reduced (ferrous) cytochrome P450

A note is that, during reduction reactions, a chemical can enter futile cycling, in which it gains a free-radical electron, then promptly loses it to Oxygen(to form a superoxide anion).


  • Esterasesand amidases
  • Epoxide hydrolase

Phase II

  • Glutathione S-transferases
    • Mercapturic acid biosynthesis
  • UDP-Glucoron(os)yltransferases
  • N-Acetyltransferases
  • Amino acid N-acyl transferases
  • Sulfotransferases

Factors that affect drug metabolism

The duration and intensity of pharmacological action of most lipophilic drugs are determined by the rate they are metabolized to inactive products. The Cytochrome P450 monooxygenase systemis the most important pathway in this regard. In general, anything that increases the rate of metabolism (e.g., enzyme induction) of a pharmacologically active metabolite will decrease the duration and intensity of the drug action. The opposite is also true (e.g., enzyme inhibition).

Various physiological and pathological factors can also affect drug metabolism. Physiological factors that can influence drug metabolism include age, individual variation (e.g., pharmacogenetics), enterohepatic circulation, nutrition, intestinal flora, or sex differences.

In general, drugs are metabolized more slowly in fetal, neonataland elderlyhumansand animalsthan in adults.

Genetic variation (polymorphism) accounts for some of the variability in the effect of drugs. With N-acetyltransferases (involved in Phase II reactions), individual variation creates a group of people who acetylate slowly (slow acetylators) and those who acetylate quickly, split roughly 50:50 in the population of Canada. This variation may have dramatic consequences, as the slow acetylators are more prone to dose-dependent toxicity.

Cytochrome P450 monooxygenase systemenzymes can also vary across individuals, with deficiencies occurring in 1 - 30% of people, depending on their ethnic background.

Pathological factors can also influence drug metabolism, including liver, kidney, or heartdiseases.


  • Basic and Clinical Pharmacology (9th Edition; Katzung): 1.4. Drug Biotransformationth:????????????????
Retrieved from "http://en.wikipedia.org/Drug_metabolism"

This article is licensed under the GNU Free Documentation License.
It uses material from the http://en.wikipedia.org/wiki/Drug+metabolism Wikipedia article Drug metabolism.

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