Pharmacogenetics is the study of how people respond differently to drug therapy based upon their genetic makeup or genes. Diet, overall health, and environment also have significant influence on medication response, but none are stronger indicators of how you will process medication than your genetics.
All drugs will eventually leave the body by a process called elimination– but the time that they stay active, in your bloodstream working, is often determined by genetic variations that change the way your drug-processing enzymes work.
How Providers use Pharmacogenetics
Utilizing Pharmacogenetics allows a healthcare provider to choose the right drug and dose that are likely to work best for each individual patient. Tailoring a patient’s medication to their unique genetic characteristics may one day replace the one-size-fits-all approach to drug selection and dosing that is commonly used today.
History of Pharmacogenetics
Pharmacogenetics is not new – An article was published in 1957 by a geneticist who noted that adverse reactions to an anti-malarial drug and a muscle relaxant were inherited and linked to deficiencies in the activity of specific liver enzymes which were responsible for the breakdown or metabolism of those particular drugs. This article established the link between genetics and the enzymes that break down medications while simultaneously establishing the link between that process and adverse reactions to the medications themselves.
The history of Pharmacogenetics may well date back to 510 B.C. when Pythagoras established a link between the eating of fava beans to the development of hemolytic anemia. This observation was later tested with modern scientific equipment and it was found that certain people, usually males, lack an enzyme which is involved in the stability of the red blood cell membrane. This deficiency is further exaggerated by the consumption of fava beans, confirming Pythagoras’s initial observations.
Pharmacogenetics Today
Currently, over 250 prescription medications contain Pharmacogenetic information in their FDA approved labels.
The label’s information contains the identification of biomarkers – the primary measurable indicators associated with a patient’s specific condition. The labels also identify targeted drug therapy specific for that genetic abnormality as well as list the genetic variations which may influence how a drug is metabolized or broken down in the body and is likely to cause a significant adverse event. The Clinical Pharmacogenetics Implementation Consortium or CPIC has created a searchable list of all medications with known pharmacogenetic implications and prescribing guidelines that can be found here.
Healthcare providers may use pharmacogenetic information to help inform the most appropriate treatment for each individual patient. This includes choosing a drug that is more likely to work, avoiding drugs that may cause side effects, adjusting the starting dose of a drug where appropriate, or determining whether closer monitoring of the drug’s effect is needed.
How does pharmacogenetics work?
The cytochrome P450 system are a family of enzymes found throughout the body which are responsible for the synthesis and metabolism of various molecules and chemicals within the cell, most notably including the active ingredient of most drugs. 
Common variations – known as polymorphisms – in the genes that determine cytochrome P450 enzyme activity may affect the function of the enzymes. These are most commonly seen in the breakdown or metabolism of medication. Drugs may be metabolized quickly or slowly. If a cytochrome P450 enzyme metabolizes a drug slowly, the drug remains active longer and a lower dose is needed to get the desired effect whereas normal doses may cause toxicity. Cytochrome P450 enzymes, particularly CYP2C9, CYP2C19, and CYP2D6, are responsible for approximately 70% of drug metabolism in the body. Additionally, there are other genes outside of the cytochrome-p450 system that affect drug metabolism and as a result – a patient’s response to medications.
Pharmacogenetic testing is primarily concerned with variations in enzymes that affect drug metabolism.
These variations are broken down into four categories based on their expected effect on drug metabolism:
- Poor
- Intermediate
- Normal
- Rapid / Ultra Rapid
Pharmacogenetics and Drug-to-Drug Interactions
Inducers are substances that affect gene expression. For example: if a drug is a CYP2D6 inducer, this will increase CYP2D6 activity which changes the way other drugs that rely on this enzyme are metabolized. Inhibitors function in the opposite way, decreasing the activity of that enzyme and potentially altering the metabolism of drugs that rely on that enzyme. This illustrates the need for an all-encompassing look at FDA approved drug-to-gene and drug-to-drug interactions.
Being aware of these inducers and inhibitors as well as monitoring for changes in the cytochrome P450 enzymes helps make pharmacogenetics a powerful force in understanding drug metabolism.
- rifampin (CYP2C19 and CYP3A)
- phenytoin (CYP3)
- ciprofloxacin (CYP1A2)
- clopidogrel (CYP2C8)
- fluoxetine (CYP2C19 and CYP2D6)
- danoprevir, ritonavir, itraconazole, clarithromycin, and grapefruit juice. (CYP3A
Glossary of Important PGx Terms
Pharmacogenetics – the study of how people respond differently to drugs based upon their genetic makeup or genes.
Genes – basic units of DNA within the cell that play an important role in heredity like determining physical traits such as eye color.
Adverse Drug Events (ADEs) – an unintended side effect caused by a medication at the time it is used.
FDA (Food and Drug Administration) – government department responsible for protecting and promoting public health through control and supervision of prescription and over-the-counter medications. Also responsible for food safety, dietary supplements, vaccines, cosmetics, and medical devices as well as other products.
Hemolytic Anemia – abnormal, early breakdown of red blood cells which may be caused by a medication reaction and lead to a low blood count. Other causes include hereditary abnormalities such as sickle cell disease, cell breakdown by artificial heart valves and very high blood pressure.
G6PD (glucose-6-phosphate dehydrogenase) deficiency – a genetic disorder seen primarily in males which causes the early or premature breakdown of red blood cells leading to hemolytic anemia.
The Clinical Pharmacogenetics Implementation Consortium (CPIC) – an international organization interested in facilitating use of pharmacogenetic tests for patient care.
Cytochrome P450 System – a group of enzymes involved in drug metabolism found in high levels in the liver. These enzymes change drugs into less toxic forms that are easier for the body to eliminate or excrete.
CYP3A4/5,CYP2C9, CYP2C19, CYP2D6 – isoenzyme systems that are part of the cytochrome P450 system and found primarily in the liver and intestines. Responsible for breaking down (metabolizing) nearly 70% of the medications we take.
Inducers – a drug which increases the activity of the enzymes of the cytochrome P450 system resulting in a decrease in the effect of certain other drugs. A dose increase of the affected drug may be necessary.
Inhibitors – a drug which decreases the activity of the enzymes of the cytochrome P450 system resulting in an increase in the effect of certain other drugs. A decrease in the dose of the affected drug may be necessary.
Poor Metabolizers – a person who breaks down (metabolizes) a drug very slowly causing a buildup of the drug within the body and potential toxicity.
Intermediate Metabolizers – a person who metabolizes a drug at a rate somewhere between a poor and extensive metabolizer. May potentially cause a buildup of the drug within the body and potential toxicity.
Normal Metabolizers – the most common type of metabolizer; one who breaks down (metabolizes) a drug at the expected or normal rate.
Rapid Metabolizers – a person who breaks down (metabolizes) a drug so fast that it will not reach optimal blood levels leading to lower than expected drug levels and an inadequate response to the drug.
Ultra-Rapid Metabolizers – a person who breaks down (metabolizes) a drug so fast that they receive no benefit from a standard dose of the drug.