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Pharmacogenomics 2, Thiopurine, 11% of population have reduced TPMT, 0.3%…

- - - - Drug transport is a complex process involving multiple factors
      - Cannot consider one aspect in isolation, e.g. transporters may have overlapping substrate specificities
      - Experiments in mouse show that intra-cerebral concentrations of antidepressant drugs regulated by this transport protein
      - Knowledge of an individuals status may prevent administration of a drug that will never reach therapeutic intra-cerebral concentrations
      - Future: use polymorphisms in transporter genes to influence treatment strategy – better patient outcome
  - - - Inhibitor of EGFR – shown to be more abundant in lung cancer tissue
      - Trials in non small cell lung cancer showed average results with a few excellent ones
      - Originally approved for treatment after failure of other options
      - Patients with excellent reactions were later shown to have a mutation in EFGR making drug more potent
- - - - Mutations may affect response to warfarin
      - The drug target is mutated, may affect interaction
      - A high inter-individual variability in dose has been shown among variants of this gene
  - - - In 2006 International Warfarin Pharmacogenomics Consortium established
      - Collected data on clinical and genetic variables to derive an algorithm to predict dose
      - Research is ongoing
- - - - Few patients studied
      - Some show mutation in an ion channel
      - Database set up to register patients who suffer from this
      - Ability to predict this kind of toxicity unlikely in near future
- - - - Variation in metabolism i.e. CYP 2C9 accounts for ~ 17% of variation in dose requirements
      - Variation in target i.e. VKORC1 explained a further 25%
      - An algorithm defined to take into account: age, body size, drug interactions and genetic variables
      - These factors can account for 54.2% of variation
      - Still essential to monitor (INR)
  - - - Glucuronidation of metabolites of irinotecan (DNA topo poison)
      - 10% of North Americans homozygous for defective alleles
      - Individuals with some mutations should not be given irinotecan
  - - - Enrol subjects according to genotype, do not use those who may have an ADR
      - Post launch monitoring:
- - - - Cytotoxic metabolite