Dvii: Outline genetic variability

Pharmacogenetics = different genotypes associated with variable expression of receptors, drug metabolising enzymes and other proteins such as transporters which results in lack of efficacy or unexpected toxicity from standard dosing of a drug

“If it were not for the great variability among individuals, medicine might as well be a science and not an art.” Sir William Osler, 1892

Sources:

  • Variation in the number of recurring small sequences in the non-coding ‘junk’ DNA
  • Single nucleotide polymorphism (SNP)

PK Variability – variability in amount of drug delivered to receptor

Metabolising enzymes

Eg CYP2D6 (Codeine, Tramadol)

  • Polymorphism of the CYP2D6 locus results in ‘poor metaboliser’ or ‘extensive metaboliser’
  • EM – abnormally high levels of M → morphine associated side effects with standard codeine dose
  • PM – poor analgesia

Drug Transporters

Eg p-glycoprotein

  • Responsible for active transport of many drugs
  • In multidrug resistant cancer cells, high transport protein activity has been identified as a resistance to therapy secondary to high levels of gene expression
  • Coded for by the MDR-1 gene (multidrug resistant gene)
  • Identifying variant MDR alleles can help treatment of patients

PD Variability – variability in response to a drug

Drug Receptors

Eg SNP of mu-receptor gene (position 118)

  • Protein produces is x3 more potent with beta-endorphon
  • May help identify individuals predisposed to opioid addiction