RLO: Pharmacogenomics
Variation In Drug Responses
Genetic factors may account for between 20 to 95% of the observed variation in drug response between individuals.
Drugs undergo five stages following administration:
- absorption into the body eg. from the gut
- distribution to their site of action in the body
- target interaction eg. binding to cellular receptors or ion channels
- metabolic processing
- excretion from the body.
Theoretically, genes that influence any stage of this pathway could affect the overall drug response.
There are two main groups of genes that are important when studying variation in drug responses. The first are those influencing the pharmacokinetic properties of drugs, such as drug metabolising enzymes and drug transporters, which affect how the drug is handled by the body. The second is those influencing pharmacodynamic properties of drugs, including drug targets such as enzymes, receptors and ion channels, and their associated pathways, which determine the drug’s effect on the body.
One example of a gene that affects pharmacokinetic drug properties is the ABCB1 gene, which encodes the MDR1 drug transporter; variants of ABCB1 are associated with resistance to the effects of drugs such as the anti-epileptic agent phenytoin.
One example of a gene that affects pharmacodynamic drug properties is the CYP2C19 gene, which encodes the metabolic enzyme cytochrome p450. Variants of CYP2C19 are associated with a decreased level of responsiveness to omeprazole, used to treat peptic ulcers and other gastric complaints.