Biotransformation/ ‘2’ main phases of drug biotransformation:


The term “drug metabolism” or “biotransformation” describes how the body changes pharmaceuticals or “xenobiotics,” or foreign substances, into more easily excretable and water-soluble forms. This change is mostly caused by the enzymes in the liver, although the kidneys, lungs, and intestines also play a part.

Two main phases of drug biotransformation:

Phase I Reactions:

Phase I reactions in drug metabolism involve the modification of a drug molecule through various enzymatic processes, making it more reactive and preparing it for subsequent Phase II reactions. These reactions typically occur in the liver and involve the introduction of functional groups or the alteration of existing ones. The three main types of Phase I reactions are oxidation, reduction, and hydrolysis.

1. Oxidation:

  • Hydroxylation: The addition of a hydroxyl group (-OH) to the drug molecule. It is one of the most common oxidation reactions. Cytochrome P450 enzymes, especially those belonging to the CYP3A and CYP2D6 families, often catalyze hydroxylation reactions.

    Example: Oxidation of benzodiazepines to form hydroxylated metabolites.

  • Dealkylation: Removal of alkyl groups (e.g., methyl, ethyl) from the drug molecule, leading to the formation of smaller metabolites. CYP450 enzymes, such as CYP1A2 and CYP2E1, are involved in dealkylation reactions.

    Example: Demethylation of codeine to form morphine.

  • Deamination: Removal of an amino group (-NH2) from the drug molecule. Monoamine oxidase (MAO) and other enzymes can catalyze deamination.

    Example: Deamination of amphetamines.

2. Reduction:

  • Reduction: Involves the addition of electrons to the drug molecule, often mediated by enzymes like cytochrome P450 reductase.

    Example: Reduction of nitro groups to amino groups.

3. Hydrolysis:

  • Hydrolysis: Cleavage of chemical bonds through the addition of water. Enzymes such as esterases and amidases catalyze hydrolytic reactions.

    Example: Hydrolysis of ester bonds in prodrugs to release the active form.

Phase I reactions generally increase the polarity and water solubility of the drug but may also yield reactive metabolites that can be toxic. The products of Phase I reactions serve as substrates for Phase II reactions, where conjugation with endogenous molecules occurs, leading to the formation of more water-soluble metabolites that are easily excreted from the body.

Phase II Reactions (Conjugation):

Phase II reactions, also known as conjugation reactions, are the second stage of drug metabolism. These reactions involve the conjugation or addition of large, water-soluble molecules to drugs or their Phase I metabolites, making them more polar and easier to eliminate from the body. Phase II reactions typically occur in the liver. Here are the main types of Phase II reactions:

1. Glucuronidation:

  • Reaction: Conjugation with glucuronic acid.
  • Enzyme: UDP-glucuronosyltransferase (UGT).
  • Example: Formation of glucuronide conjugates, such as morphine-3-glucuronide.

2. Sulfation:

  • Reaction: Conjugation with sulfate.
  • Enzyme: Sulfotransferase.
  • Example: Formation of sulfate conjugates, often involving phenols and alcohols.

3. Methylation:

  • Reaction: Addition of a methyl group (-CH3).
  • Enzyme: Methyltransferase.
  • Example: Methylation of catecholamines like dopamine to form metanephrine.

4. Acetylation:

  • Reaction: Conjugation with an acetyl group (-COCH3).
  • Enzyme: N-acetyltransferase (NAT).
  • Example: Acetylation of isoniazid.

5. Conjugation with Amino Acids:

  • Reaction: Conjugation with amino acids like glycine.
  • Example: Conjugation of benzoic acid with glycine to form hippuric acid.

6. Glutathione Conjugation:

  • Reaction: Conjugation with glutathione.
  • Example: Detoxification of reactive metabolites, such as in the case of acetaminophen metabolism.

These conjugation reactions result in the formation of larger, more polar metabolites that can be easily excreted in urine or bile. The addition of these groups also serves to mask or neutralize any remaining pharmacological activity of the drug or its metabolites. Phase II reactions are essential for the detoxification and elimination of drugs from the body.

The combined action of Phase I and Phase II reactions ensures that drugs are adequately transformed into water-soluble forms, allowing for efficient elimination through the kidneys or bile. Variations in individual genetic makeup can influence the activity of enzymes involved in these reactions, leading to interindividual variability in drug metabolism.

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