Pharmacogenetics – inherited variability in drug response

Adverse drug reactions are the fourth leading cause of death in the developed world. Many adverse drug reactions occur at standard manufacturer doses.

The lecture will introduce:

• drug metabolism
• the importance of phase 1 and phase 2 metabolism in the detoxification of drugs
• phase 1 metabolism prepares a drug for phase 2 detoxification by inserting a functionally reactive group onto the drug

e.g. the Cytochrome P450 (CYP) family. CYP2D6 metabolizes 25% of all therapeutic drugs. Three CYP2D6 phenotypes are observed: poor metabolisers, extensive metabolisers and ultra rapid metabolisers. The consequences of each phenotype for drug therapy will be described.

• phase 2 metabolism prepares a drug for excretion by conjugating a small hydrophilic molecule to the drug

e.g. N-acetyl transferase family. NAT2 acetylates a number of drugs thereby increasing their hydrophilicity and aiding the excretion of the drug through the bile and urine. Rapid and slow acetylators have been identified.

• The future – personalised prescriptions – Adverse drug reactions could be largely prevented if individuals were genotyped/phenotyped for polymorphisms in drug metabolizing enzymes. This would also diminish the largest source of malpractice payouts in the USA.

Introduction to Drug Metabolism – G. Gordon Gibson and Paul Skett – Blackie Academic & Professional

Emery’s Elements of Medical Genetics (11^th Edtn) Mueller, R.F. and Young, I.D.

Meyer, U.A. (2000) Pharmacogenetics and adverse drug reactions The Lancet 356:1667-1671.

Roses, A.D. (2000) Pharmacogenetics and the practice of medicine Nature 405:857- 865.

Roses, A.D. (2001) Pharmacogenetics Human Molecular Genetics 10: 2261-2267