Cytochrome enzymes metabolism

1
Cytochrome enzymes metabolism

• Genetic variation in processes involved in the
  absorption, distribution, metabolism, or
  elimination of a drug can result in changes in
  drug availability.
• Atomoxetine is metabolized by the Cytochrome P50
  system, particularly CYP-2D6.
• Poor metabolizers (approximately 5-10 of the
  North American population) achieve 2-3 fold
  higher peak plasma concentrations of atomoxetine.
  
• The mean plasma half-life of the drug is 5.2
  hours for extensive metabolizers and 21.6 hours
  for poor metabolizers

Simpson Perry (2003). Paediatric Drugs, 5(6),
407-415).
2
Selected Substrates of CYP 2D6

• Antidepressants
• Amitryptiline
• Clomipramine
• Imipramine
• SNRIs-SSRIs and comb.
• Atomoxetine
• Duloxetine
• Flouxetine
• Fluvoxamine
• Paroxetine
• Venlafaxine

• Antipsychotics
• Chlorpromazine,
• Haldol
• Risperidone
• Cough and allergy
• Chlorpheniramine
• Codeine
• Dextromethorphan
• Beta blockers
• Metoprolol
• Propanolol

3
CYP 2D6 Selected Inhibitors and Inducers

• Inhibitors
• Bupropion
• Cimitidine
• Clomipramine
• Escitalopram
• Fluoxetine
• Paroxetine
• Sertraline

• Inducers
• Dexamethasone
• Rifampin

4
Summary

• ADHD pharmacogenetics and pharmacogenomics are
  still in early stages
• There is optimism that advances in
  pharmacogenomics may inform treatment response
  and predict vulnerability to adverse events.
• Understanding of protein expression and function
  may lead to better diagnostic markers and the
  development of custom-made therapeutic agents
• Hopefully, genomics, proteomics and metabonomics
  in pharmacology wont just be 'fashionomics

5
Resources

• http//www.pharmgkb.org
• PharmGKB is an integrated resource about how
  variation in human genes leads to variation in
  our response to drugs
• http//medicine.iupui.edu/flockhart/http
• Information on Cytochrome P50 system and
  potential drug interactions