Metabolism

Metabolism

1. Liver

   • Feeder
     • Gut absorbtion
       • Hepatic portal
       • Must escape
       • First pass metabolism
         • Variable
     • All bloodstream
   • Most important

2. Gut

   • GI tract
     • Gut bacteria
     • Proteases
   • Intestinal wall
     • CYP's
     • Some metabolism

3. Blood

   • enterases

4. Tissues

   • Monoamine oxidase in neurones

5. Results

   • More water soluble
     • Less likely to enter cell
     • Easier to excreet
   • Inactivates most drugs
     • Prodrugs activated (acetyl salycilic acid)
     • No change (diazepam to nordiazepam)
     • Toxic metabolites (paracetamol)

6. Reactions

   • Phase 1
     • Addition or uncover reactive group
     • Sets up phase 2
     • Reactions
       • Oxidation
         • Most important
         • Cytochrome P450
           • Located on smooth ER
           • CYP isosymes in most metabolism
         • O2, NADPH and P450
       • Reduction
       • Hydrolysis
   • Phase II
     • Usually second
     • Conjugation with endogenous
     • Glucoronide
       • Addition of glucose
       • Active transport targeted
       • Large changes
     • Sulphate
     • Amino acids / glutathione
     • Acetylation / methylation
   • Phenytoin
     • Highly lypophyllic
       • Enters brain
       • Active
     • CYP hydroxylates in liver
       • Slightly soluble in water
       • Inactive
       • Phase 1
     • Glucoronisation
       • Phase II
       • Uridine diphosphate glucoronide
       • Very water soluble
       • Excreted by kidney
     • Anti-epileptic

7. Fates

   • Large = bile to faeces
   • Small = kidney
   • Weight dependant

8. Variation

   • Huge and dynamic
   • Personal
     • Genetics
     • Age
       • Neonates
         • Theophylline
           • Asthma
           • Apnoea
         • 1/2 life
           • Reduces over days
           • 60 days at birth
           • Grows/matures enzymes
           • 6 hours at 200 days
       • Years
         • Clearance decreases with time
         • Slight loss of function
         • Individual variation is greater
         • Dosage is hard
       • Children are very efficent
     • Gender
       • Not normally significant
       • Males more efficent
       • Huge personal variaton
       • Propranolol
     • Pregnancy
   • Organ function
     • Liver
     • Kidney
     • Heart
     • Gut
   • Disease
     • Liver failure
   • Drug activatiors
     • Barbituates
     • Phenytoin
     • Rifampicin
     • St John's wort
       • Reduces cyclosporin
       • Liver transplant
   • Enviroment
     • Diet inducers
       • BBQ meat
       • Cruciferous vegetables
       • Low alcohol
       • High protien diet
       • Insecticides (DDT)
       • Polychlorinated biphenyls (insulators)
     • Cigarettes
       • Liver c450 primed
       • Theophylline
         • Control 6-10 h half life
         • Smokers 4-6 h half life
         • 50% higher dosage
       • Cafffene
         • Reduced
         • Huge personal range
   • Liver activity
     • Optimisation
       • Starts in 24H
       • Increases 3-5 days
       • 1-3 week reversion
     • Removes drug
     • Cross reactivity common
   • Metabolism inhibition
     • Rapid onset (within 1 day)
     • Potential of death by overdose
     • Reversible C450
       • Cimetidine (reflux)
       • Ketoconazole (antibiotic)
       • Quinolones (antibiotics)
       • HIV inhibitors
       • Grapefruit juice
       • Heavy metals
         • Complex p450
         • Pb, Cd, Hg

9. Lipid soluble elimination

10. Warfarin

    • Cimetidine inhibits
      • Level rises
      • Anti-coagulant increases
    • Phenobarbatone
      • Enzyme synthesis
      • Warfarin tracks down
    • From steady state
      • Time taken to rise
      • Falling takes time

11. Population response

    • Most is metabolism
    • 1/5 no response
    • 1/5 adverse overdose
    • 3 therapeutic benefit