Many medicines are currently prescribed as though they work equally well in all people, or the dose is adjusted depending on the age, size, or gender of a patient. However, even if patients are the same age, size or gender, they may still have different responses to the same medicine because of genetic variation.
The impact of our human genome on drug metabolism is significant – that is why national agencies are starting to include pharmacogenomic information in the dosing guidance on drug labelling. For instance, just one liver enzyme, CYP2D6, acts on a quarter of all prescription drugs. For example, it converts the painkiller codeine into its active form, morphine. This gene has many potential genetic variants, 160 according to the NIH. These variants can have significant impact on how effective the relevant drugs can be for a person, and as each person is unique, the effect can be different depending on each person’s particular genetic variations.
Pharmacogenomic testing gives insight into how an individual patient may respond to a medicine. As a result, the choice or dose of a medicine can be tailored to that individual, personalising their treatment. By prescribing medication based on a patient’s genetics, that patient is more likely to get a treatment that works.
Genetic variation affects whether a patient has a bad reaction to a medicine or how well a patient responds to a medicine by changing a drug’s pharmacokinetics and pharmacodynamics. Genetic variation in genes encoding proteins involved in a drug’s pharmacokinetics can alter how a drug is metabolised. If a drug is metabolised too quickly, it might not be as effective. Alternatively, if the drug is metabolised too slowly, it may build up in the body and cause dangerous side effects.
Genes involved in a drug’s pharmacodynamics can encode proteins that the drug may need to bind to in order to have an effect on the body. Genetic variation can change the structure of a protein, affecting how well the drug binds to the protein. This can change how well the drug works. Genetic variation in different types of genes can affect pharmacokinetics and pharmacodynamics in different ways:
Drug transporters: Transporters move molecules in and out of cells. Variation in genes encoding drug transporters can affect their function, changing how well drugs can enter or exit cells and increasing or decreasing concentrations of a drug in different parts of the body. If the concentration of the drug at the site of action is too low, the drug may not work as well. If the drug concentration becomes too high, it could cause toxic side effects. Example genes are SLCO1B1, ABCB2, ABCG2.
Drug metabolising enzymes: Variation in drug metabolizing enzymes can affect how quickly a drug is broken down in the body. This can have different effects depending on the specific drug. If an active drug is metabolized too quickly, it will be inactivated too quickly and may not work well. If it is metabolized too slowly, toxic concentrations of the drug might build up. Alternatively, some drugs have to be metabolized in order to become active. For drugs like these, being metabolized too quickly increases the concentrations of active molecules in the body and increases the risk of toxic side effects while being metabolized too slowly can reduce how effective the drug is. Example genes in this category include cytochromes (CYP2C9, CYP2D6 and so on).
Pharmacogenomics is also a great example of how, while one’s underlying genetic code more or less set from birth, the usefulness of the analysis changes over one’s lifetime. For instance, if a patient is apparently healthy, it might seem absurd to talk to them about potential Warfarin dosing, or which cancer drugs might or might not be effective for them. But this is information could become extremely valuable at a different point in life, and knowing this kind of thing in advance allows individuals to be empowered with information which will help them later. Also, in the unhappy event that a patient is confronted with a particular illness, it’s easy to go back and ask the genome questions about drugs that might or might not be applicable to that illness. So in that way, a person’s genome becomes a valuable resource for them to refer back to as their circumstances change.