Lecture 1

• Pharmacogenetics


  Study of unusual responses to drugs and other foreign compounds that have hereditary basis
• Pharmacogenomics


  • Individualisation of drug therapy using information from human genome project
  • Relies on using information from gene sequencing
• Genetic polymorphisms


  • A mutation that occurs at a population frequency of at least 1 in 100
  • Can be base substitution (SNP), insertion or deletion
  • Polymorphisms occur approx every 1 in 1000 bases but most do not have a functional effect
• Functional polymorphisms


  • Effect on biological activity often due to:
  • Amino acid substitution
  • Effect on transcription factor binding
  • Altered splice site
• Toxicity


  • Exaggerated response or effect on inappropriate target
  • Depends on therapeutic window
• Lack of response


  • Target doesn't respond or drug metabolised or excreted too rapidly
  • Prodrug not activated
• Phenotypic approaches


  1. Information about physical characteristic

  2. Enzyme activity

  3. Pattern of drug metabolism
• Limitations of phenotypic approaches


  • Enzyme measurements problematic - tissue needs to be accessible
  • Studies on patterns of drug metabolite difficult — need a suitable prodrug or chemical and good analytical technique
  • Difficult in studies of drug receptors
• Genotypic approaches


  1. Study gene of pharmacological relevance for the presence of genetic polymorphisms

  2. Examine phenotypic effect - in vitro or in vivo applications
• Advantages of genotypic approaches


  • Look directly at gene of interest
  • Can use blood sample, buccal cells, or saliva as a source of DNA (WBC best quality)
• Disadvantages of genotypic approaches


  • May need to relate polymorphisms to function - technically complex
  • Techniques and algorithms available to predict functional effects on protein structure and activity