English

METABOLISM

Definition : "Drug biotransformation, generally into more polar compounds readily excreted from the body through urine or feces."

Description

Metabolic biotransformations can occur between absorption of the drug into the general circulation and its excretion. Metabolic products are often less active pharmacodynamically than the parent drug and may even be inactive. However, some metabolites have enhanced activity or toxic properties.

Drug metabolism usually occurs in the liver, but occasionally can take place in the gastrointestinal tract, lungs, kidneys, skin or plasma.

Two phases in metabolism are classically recognized:

  1. Phase I: Transformation of drug into a more polar metabolite by introducing or unmasking a functional group (e.g. oxidation, reduction or hydrolysis). Oxidation reactions are often catalyzed by a member of the cytochrome P450 family. These enzymes are mostly located in the endoplasmic reticulum of the hepatocytes (microsomial enzymes).
  2. Phase II: Combination of a glucuronic acid, sulfuric acid, acetic acid or amino acid with a functional group to form a polar conjugate that can be readily excreted in urine or feces. The enzymes catalyzing these reactions are mostly located in the cytosol of the hepatocytes.

These two phases often occur sequentially: phase I oxidation prepares a functional radical enabling the conjugation with a polar compound.

Clinical implications

Metabolic reactions widely vary from one individual to another, and consequently affect the dose and frequency of administration required to achieve effective and safe drug levels in the organism. Genetic polymorphism accounts for some of the differences observed. Other important factors determining metabolism are age, diet, environmental factors, drug-drug interactions and diseases affecting metabolism (e.g. acute or chronic liver, cardiac or renal disorders).

Related terms

Prodrug

Enzyme induction: Acceleration of metabolism by increase of enzyme expression. Various substrates appear to induce metabolism, such as certain drugs and environmental pollutants. Induction decreases the pharmacological action of the substrate of the enzyme, including frequently the inducer. Sometimes, the enhanced amount of metabolites can increase toxicity or carcinogenicity.

Enzyme inhibition: Competitive blockade or inactivation of the enzyme by a substance, which may or may not be a substrate. The inhibition increases concentrations of the parent drug, and thus exaggerates and prolongs its pharmacological effects. For prodrugs, inhibition may decrease the pharmacological response.

Hepatic first pass effect: All drug dose absorbed from the gastrointestinal tract is first delivered to the liver by the portal vein. A fraction of the drug can then be metabolized in the liver before it even reaches the systemic circulation. Therefore the oral bioavailability of the drug is reduced.