Biotransformation | Drug Metabolism

Biotransformation | Drug Metabolism

What is Biotransformation?

drug molecules

Introduction

Biotransformation is chemical alteration of the drug in the body

Steps in Biotransformation Reaction

  1. Inactivation
    • More drugs and there active metabolites are rendered inactive or less active
  2. Active metabolite from inactive drug
    • Many drugs are found to be partially converted to one or more active metabolites
    • The effects observed are the sum total of that due to the parental drug and its active metabolites
  3. Activation of inactive drug
    • Few drugs are inactive and requires conversion in the body to one or more active metabolite
    • These drugs are called Prodrugs, which offers advantage over the active form in being more stable, having better bioavailability or other desirable pharmacokinetic properties
    • Prodrugs show less side effects and toxicity

Classification of Biotransformation Reaction

  • Nonsynthetic Reaction
    1. Oxidation
      • It involves addition of oxygen (negatively charged radical) or removal of hydrogen (positively charged radical)
      • It is most important drug metabolizing reaction
      • It is carried out by a group of monooxygenase in liver which are Cytochrome P-450 haemoprotein, NADPH, cytochrome P-450 reductase and molecular O2
      • eg. Barbiturates, Paracetamol, Phenothiazines, Steroids, Adrenaline
    2. Reduction
      • It is converse of oxidation reaction
      • It involves cytochrome P-450 in opposite direction
      • eg. Chloramphenicol, Halothane, Warfarin
    3. Hydrolysis
      • It shows breakdown of drug molecule by taking up a water molecule
      • Sites for hydrolysis are liver, intestine, plasma
      • eg. Choline esters, Procaine, Lidocaine, Oxytocin
  • Synthetic Reaction
    1. Glucuronide Conjugation
      • It is carried out by a group of UDP-glucuronosyl transferase (UGTs)
      • Compounds with hydroxyl or carboxylic acid are easily conjugated with glucuronic acid
      • eg. Chloramphenicol, Aspirin, Morphine, Metronidazole
    2. Acetylation
      • Compounds having amino or hydralazine residue are conjugated with the help of acetyl coenzyme-A
      • eg. Sulfonamides, Isoniazid, Hydralazine
    3. Methylation
      • Amines and phenols can be methylated
      • Methionine and cysteine acts as methyl donors
      • eg. Adrenaline, Histamine, Nicotinic acid
    4. Sulfate Conjugation
      • Phenolic compound drugs are sulfated by sulfotransferase
      • eg. Chloramphenicol, Steroids
    5. Glycine Conjugation
      • Drugs having carboxylic acids are conjugated with glycine
      • eg. Salicylates
    6. Glutathione Conjugation
      • It serves to deactivate highly reactive quinone or epoxide intermediates formed during metabolism of certain drugs
      • eg. Paracetamol
    7. Ribonucleoside / Nucleotide Synthesis
      • It is important for activation of many purine and pyrimidine antimetabolites used in cancer chemotherapy

Types of Drug Metabolizing Enzyme

  1. Microsomal
    • These are located on smooth endoplasmic reticulum eg. Liver, Kidney, Intestinal mucosa, Lungs
    • eg. Monooxygenase, Cytochrome P-450, UGTs
    • They catalyst most of the oxidation, reduction, hydrolysis, and glucuronide conjugation
  2. Nonmicrosomal
    • These are located in cytoplasm, mitochondria of hepatic cells
    • eg. flavoprotein oxidase, esterase, amidase and conjugase
    • They catalyst oxidation, reduction and hydrolytic reactions

Hoffman Elimination

It refers to inactivation of the drug in the body fluids by spontaneous molecular rearrangement without the agency of any enzyme eg. atracurium