Drug metabolism: enzymatic conversion of the drug to another chemical entity

Overview of drug metabolism

Drugs are xenobiotics - drug metabolism acts to:

• Convert parent drugs to more polar metabolites that are not readily reabsorbed by the kidney (from the renal tubules), facilitating excretion
• Convert drugs to metabolites that are usually pharmacologically less active than the parent compound
• Less frequently, metabolites may:
  • Be converted from inactive prodrugs to active compounds or gain activity
  • Have unchanged activity
  • Possess a different type, or spectrum, of action
• The main organ of drug metabolism is the liver, but the GI tract, lungs, and plasma also have activity

Phases of drug metabolism

• Liver is the most important metabolic organ (kidney, gut mucosa, lungs and skin also contribute)
  • Phase I and phase II both take place in liver

Phase 1 metabolism

• Phase I metabolism: change in the drug by oxidation, reduction or hydrolysis
• Usually results in pharmacologically active and/or toxic metabolites

Oxidation

• Accomplished by cytochrome P450 enzymes
  • Haem proteins located in the endoplasmic reticulum of liver hepatocytes mediating oxidation reactions (phase 1) of many lipid soluble drugs
  • Comprise a ‘superfamily’ (74 gene families) - classified as CYP by following a defining number of numbers and letters
  • Have distinct, but frequently overlapping substrate specificities
  • The main gene families in the human liver are CYP1, CYP2 and CYP3
  • Activity is genetically determined
    • Some people lack activity - higher drug plasma levels (adverse actions)
    • High levels of activity = reduced drug action
  • Other drugs can interact with P450 system – increase or decrease activity
• Drug molecule incorporates an atom of oxygen to form a hydroxyl group

The monooxygenase P450 cycle

1. Drug enters cycle as drug substrate, RH
2. Molecular oxygen (O2) provides two atoms of oxygen
3. One atom of oxygen is added to the drug to yield the hydroxyl product, ROH, which leaves the cycle, the second oxygen combines with protons to form H2O