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