Biotransformation Notes

Biotransformation Overview

  • Biotransformation involves the molecular alteration or transformation of drugs within biological systems, making them suitable for excretion.

Purpose of Biotransformation

  1. Conversion of Active Drug to Inactive
    • Example:
      • Phenobarbitone → Parahydrxyphenobarbitone
      • Morphine → Morphine glucuronide
  2. Conversion of Inactive Drug to Active
    • Example:
      • Cortisone → Cortisol
      • Levodopa → Dopamine
  3. Conversion of Active Drug to Active Metabolite
    • Example:
      • Diazepam → Desmethyle diazepam
      • Codeine → Methyl codeine
  4. Conversion of Toxic Substances to Non-toxic

Processes of Biotransformation

  • Phase-1 Reactions:

    • Include Oxidation, Reduction, Hydrolysis
    • Types: Micromodal and Non-microsomal

  • Phase-2 Reactions:

    • Conjugation reactions: Glucuronidation, Acetylation, Methylation, Glycin and Sulfate Conjugation

Characteristics of Phase I Reactions

  • Alteration of the parent drug by introducing or unmasking functional groups (-OH, -COOH, -SH).
  • Often causes loss of pharmaceutical activity and can convert inactive prodrugs into active forms.

Fate of Phase I Reactions

  1. May pass through urine.
  2. React with water-soluble compounds to form water-soluble conjugates.

Requirements for Phase I Reactions

  • Enzymes: Microsomal and Non-microsomal types
  • Key Enzymes: Cytochrome P-450 oxidase, Mixed function oxidase, Reducing agent (NADPH)

Characteristics of Phase II Reactions

  • Conjugation Reaction: Parent drug participates in forming a conjugate substrate which facilitates drug elimination.
  • Inactivation of electrophilic and potentially toxic metabolites produced by oxidation.
  • Required Enzymes:
    • GDP glucuronyl transferase
    • Glutathione-S-transferase
    • N-acetyltransferase
    • Methyltransferase

Sites of Biotransformation

  • Main Site: Liver
  • Other Sites: GIT, Lung, Skin, Kidney
  • Location: Smooth surface of the Endoplasmic Reticulum, Mitochondria, Lysosomes, Nuclear envelope, Plasma membranes

Types of Biotransformation Enzymes

  1. Microsomal Enzymes
    • Located in the liver cells.
    • Mixed-function oxygen systems or monooxygenases requiring NADPH and oxygen.
  2. Non-Microsomal Enzymes
    • Found in cytoplasm and mitochondria of liver cells and also in plasma and other tissues.

Enzyme Induction and Inhibition

  • Induction: Increased synthesis of microsomal enzymes can enhance drug metabolism by specific drugs and environmental pollutants leading to clinically significant drug interactions.

    • Examples: Phenobarbitone, Phenytoin, Alcohol, Environmental pollutants.

  • Inhibition: Some drugs inhibit cytochrome P450 enzymes, affecting drug metabolism and resulting in drug interactions. Examples include Cimetidine and Erythromycin.

Factors Modifying Biotransformation

  1. Physiological Factors: Age, Sex, Body Weight, Hormonal influences.
  2. Nutritional Status: Effects of starvation or malnutrition.
  3. Pathological Conditions: E.g., liver diseases can alter metabolism.
  4. Genetic Factors: Variability in metabolic enzyme function based on genetics.
  5. Environmental Factors: Impact of pollutants on enzyme activity.
  6. Species Differences: Variability in drug metabolism across different species.

Examples of Biotransformation Reactions in Drugs

  • Various reactions like oxidation (hydroxylation, hydrolysis, etc.), acetylation, and conjugation of various pharmaceuticals leading to changes in their activity and excretion pathways.