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Pharmacogenetics

Sarah Ball Department of Clinical Chemistry Birmingham Children’s Hospital. Pharmacogenetics. Definitions. Pharmacogenetics Study of genetic variation (specific genes)  differing drug responses Pharmacogenomics

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Pharmacogenetics

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  1. Sarah Ball Department of Clinical Chemistry Birmingham Children’s Hospital Pharmacogenetics

  2. Definitions • Pharmacogenetics • Study of genetic variation (specific genes)  differing drug responses • Pharmacogenomics • Genome-wide study of influence of heredity on drug repsonse (e.g. identify new drug targets, genomic factors involved in optimising drug therapy)‏

  3. Why study pharmacogenomics/genetics? • Drug metabolism is highly complex involving variety biochemical pathways • Potentiate • Activate • Breakdown or de-toxify • Eliminate • Effectiveness of drug • Adverse drug reactions

  4. History of pharmacogenetics • 1950s • Pseudocholinesterase deficiency • Suxamethonium - muscle relaxant used in anaesthesia • Metabolised by pseudocholinesterase E1(CHE1)‏ • ~1 in 3500 N Europeans have CHE1 deficiency • Deficiency of CHE1 activity causes prolonged post-anaesthetic apnoea (2-3 hours)‏ • A dibucaine inhibition test was used to test for CHE1 deficiency • Kalow, W.; Genest, K. A method for the detection of atypical forms of human cholinesterase: determination of dibucaine numbers. Canad. J. Biochem. Physiol. 35: 339-346, 1957

  5. N-acetyl transferase (NAT2)‏ • Arylamine N-acetyl transferase involved in metabolising many drugs • isoniazid - anti-tuberculosis agent • procainamide - anti-arrhythmia agent • “Slow” and “fast” acetylators refers to rate at which xenobiotics are inactivated (processing activity of enzyme)‏ • Drug half-life • Circulating drug concentration • Slow is recessive to fast • Tested by acetylation of sulfamethazine

  6. Cytochrome P450 family of enzymes • Large family of liver enzymes • Detoxify xenobiotics for urinary excretion • Polymorphic • Reduced activity/inactive variants • Gene duplications  accelerated activity

  7. Role of CYP2D6

  8. Pharmacogenetics has been around a long time • Can be used to determine patient’s response to drugs (improve patient safety)‏ • Can be used to determine appropriate drug and dose for patient (improve cost-efficacy of drug bill)‏ • Testing possible • Biochemical tests probably not cost-effective but molecular genetic tests could be • Why are these tests not routine?

  9. Should we test? • Who should test? • Pharmacy labs • Molecular genetics diagnostic labs • Drug company labs

  10. Resources • See: • http://www.geneticseducation.nhs.uk/ • Brilliant citations and weblinks

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