Drug Metabolism Principles: Phase I and Phase II

Drug Metabolism Principles Definition 

• Drug Metabolism Principles: Drug metabolism is the biochemical modification of pharmaceutical substances in the body, primarily carried out by liver enzymes.
• It occurs in two main phases:

Phase I Metabolism

Overview:

• Phase I reactions modify drug molecules via oxidation, reduction, or hydrolysis, often introducing or exposing functional groups (-OH, -NH₂, -SH).

Common Reactions:

1. Oxidation

   • Most common Phase I reaction
   • Catalyzed mainly by cytochrome P450 (CYP450) enzymes, found predominantly in the liver but also in the intestines and other tissues.
   • Oxidation involves adding an oxygen atom or removing a hydrogen atom from the drug molecule.
   • Examples of oxidative reactions:
     • Hydroxylation (adding -OH)
     • Dealkylation (removal of alkyl groups)
     • Sulfoxidation (oxidation of sulfur-containing compounds)

2. Reduction

   • Involves the gain of electrons or the loss of oxygen.
   • Common with nitro compounds, azo compounds, and certain carbonyl groups.

3. Hydrolysis

   • Involves the cleavage of chemical bonds by the addition of a water molecule.
   • Catalyzed by esterases and amidases, which hydrolyze esters and amides, respectively.

Outcome of Phase I Reactions

• Metabolites may be more active, less active, or equally active compared to the parent drug.
• Some Phase I metabolites can be toxic.
• Many Phase I metabolites undergo further modification in Phase II metabolism.

Effects on Drugs:

• Activation: Converts prodrugs into active forms.
• Inactivation: Renders some drugs ineffective.
• Reactive Metabolites: Can form toxic intermediates, requiring further detoxification.

Phase II Metabolism

Overview:

• Phase II conjugation reactions attach endogenous molecules (e.g., glucuronic acid, sulfate, glutathione) to drugs or Phase I metabolites.

Common Reactions:

1. Glucuronidation

   • Most common Phase II reaction
   • Catalyzed by uridine diphosphate glucuronosyltransferase (UGT).
   • Adds glucuronic acid to drugs or metabolites.
   • Produces highly polar and water-soluble conjugates, which are excreted in urine or bile.

2. Sulfation

   • Catalyzed by sulfotransferases (SULT).
   • Transfers a sulfate group to phenols, alcohols, and amines.
   • Increases water solubility, aiding excretion.

3. Acetylation

   • Catalyzed by acetyltransferases.
   • Transfers an acetyl group from acetyl coenzyme A to the drug.
   • Common with amines (e.g., isoniazid).

4. Methylation

   • Involves the addition of a methyl group (-CH₃).
   • Catalyzed by methyltransferases.
   • Usually occurs at oxygen, nitrogen, or sulfur atoms.

5. Glutathione Conjugation

   • Important for detoxification of electrophilic compounds.
   • Results in the formation of glutathione (GSH) conjugates, which are later excreted in urine or bile.

Outcome of Phase II Reactions

• Increased water solubility, leading to rapid elimination.
• Typically results in inactive metabolites.
• In rare cases, Phase II reactions can produce active or toxic metabolites.

Benefits of Conjugation:

• Enhances excretion via kidneys or bile.
• Reduces pharmacological activity and toxicity.
• Neutralizes harmful metabolites.

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