Drug Metabolism I - MOOC Quiz

Drug Metabolism I - Lecture Topics

• Phase 1: Basic Principles of Drug Metabolism (DM)
• MOOC (Massive Open Online Course)

Course Objectives

• Comprehend, apply, and evaluate the key concepts and principles of drug metabolism.
• Identify and characterize major metabolites of a given drug and the specific enzymes involved in its metabolism.

The Fate of a Drug

• Drugs begin with a dose.
• Absorption to the body occurs.
• Distribution is to most tissues and then to plasma where some is protein-bound and some is free.
• Metabolism occurs, and the drug is eliminated through renal excretion.
• Distribution also occurs to the biophase where receptor binding results in an effect.
• These processes are grouped in Pharmacokinetics and Pharmacodynamics.

Stages of Drug Metabolism

• Absorption: Drug travels to the site of administration, moves into the bloodstream.
• Distribution: Drug moves throughout the body. The drug/metabolites move into the tissues.
• Metabolism: Drug/metabolites change in tissues.
• Elimination: Drug/metabolites are removed from the body in urine, feces, or bile.

Drug Metabolism

• Metabolic breakdown of drugs by living organisms (xenobiotics), mostly in the liver.
• Converts lipophilic compounds to hydrophilic compounds for easier excretion.
• Can turn procarcinogens into toxic mutagens.
• Individual variations in factors (genetics, physiology) significantly impact metabolic rates, and the metabolism of one xenobiotic may influence the metabolism of others.

Metabolism in Non-Hepatic Tissues

• Intestinal mucosa (GI tract)
• Kidney
• Lung
• Bacteria in the GI tract are involved in drug metabolism.

First-Pass Metabolism

• A major process of metabolism that happens in the liver and intestinal tract before reaching the general circulation.
• Metabolism happens in the gut which results in inactive metabolites.

Drug Metabolism Pathways

• Phase 1: Introduces or uncovers polar groups (such as CO₂, OH, or NH₂) via oxidation, reduction, or hydrolysis.

• Phase 2: Links an endogenous moiety (like GSH, sulfate, glycine, glucuronic acid) to the original drug or phase 1 metabolite. This creates polar metabolites which cannot cross membranes and are excreted.

• Phase 3: Conjugated xenobiotics are processed further, recognized by efflux transporters, and removed from the cells.

Drug Metabolism Example-Morphine

• A hydrophobic drug that is metabolized via Phase 1 (demethylation) & Phase 2 (glucuronidation) to become more hydrophilic and excreted.

Implications of Drug Metabolism

• Termination of drug action
• Activation of prodrugs
• Bioactivation and toxification
• Carcinogenesis

Two Xenobiotic Categories

• Hydrophilic compounds (like saccharin, strong acids, or bases) are largely unaffected by metabolic transformations.

• Highly lipophilic compounds (like DDT): Many metabolic reactions often do not lead to inactivation or detoxification, instead, some metabolites can be as potent as the original, bind covalently to proteins, DNA, and cause mutagenesis/carcinogenesis.

Lethal Synthesis

• The metabolic conversion of non-toxic Parathion to paraoxon, a potent acetylcholinesterase inhibitor.

Major Sites of Metabolism

• Drug metabolism occurs in various tissues, but the liver is the primary organ for metabolism, followed by the lungs, kidneys, and intestine, respectively. The CNS has very low metabolic activity.

• The liver, due to high blood flow and numerous metabolic enzymes, is the primary site of drug clearance:

  - High: liver
  - Medium: lungs, kidneys, intestine
  - Low: skin, testes, placenta, adrenals
  - Very low: CNS
  

• Extrahepatic microsomal enzymes and non-microsomal enzymes (like hepatic enzymes) also contribute to the metabolism.