Elementary Drug Metabolism

Drug metabolism

  • Drug metabolism: enzymatic conversion of the drug to another chemical entity
  • 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
  • Metabolism in liver (+ gut) reduces bioavailability of drugs when administered orally
  • Hepatic drug metabolizing enzymes are embedded in the SER of hepatocytes
  • Non-polar drugs can more easily cross membrane to be metabolized

Phase I 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
    • Family of haem proteins
    • 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

Cytoplasmic enzymes

  • Can metabolise drugs

Hydrolytic reactions

  • Ester and amide bonds are susceptible to hydrolysis

Phase II metabolism

  • Phase II metabolism: involve the combination of the drug with one of several polar molecules to form a water-soluble metabolite - conjugation
    • Usually involves the reactive group produced by phase I
    • Usually terminates all biological activity
    • Products can be readily excreted via kidneys
  • Some drugs (e.g. codeine) can go directly to phase II metabolism
    • Can produce metabolites that are pharmalogically active

Glucuronidation

  • Enzyme - uridine disphosphate-glucoronosyltransferases
  • Cofactor - uridine diphosphate glucuronic acid