Gene variations, or differences, are a major reason why people respond differently to drugs. In fact, genetic factors account for 20 to 95 percent of the variability in drug response. Genes are important because they encode the enzymes needed for drug metabolism and proteins that determine the cellular response to drugs. Certain genetic variants can lead to differences in the functional proteins that are coded by the gene, consequently changing the way that the drug is processed in the liver or in the molecules that are targeted by the drug.
As everyone responds differently to medications, the field of pharmacogenetics (i.e., pharmacogenomics or drug-gene testing) has played an important role in helping physicians and other health care professionals choose medications that will work best for each patient by examining the genetic variations, or differences, in an individual’s DNA. The genetic variations are examined by collecting a small blood or saliva sample from the patient. If a patient is found to have certain genetic variants, this information can then be used to determine the medication that he or she will respond to best with the fewest adverse side effects.
What is pharmacogenomics?
Pharmacogenomics is an important tool for determining how the body will process and respond to certain medications based on the variants in an individual’s genetic makeup. Knowing whether a patient has certain genetic variations in his or her DNA can be useful for choosing the medications that will work best for each patient, decreasing the number of potential adverse drug reactions and increasing the drug’s effectiveness for that individual. Health care providers who have knowledge of a patient’s genetic variants can tailor their treatment options while also taking into account the patient’s history, behavior and environment.
How do gene variants affect drug response?
Variants in genes can affect the pharmacokinetic (PK) or pharmacodynamic (PD) drug response pathways. Pharmacokinetic refers to the way that the body moves the drug into, through and out of the body (e.g., absorption, distribution and metabolism), while pharmacodynamic refers to the biochemical and physiological effects of drugs on the body (e.g., mechanisms of drug action, relationship between drug concentration and effect, etc.). Following drug administration, the drug goes through five stages:
- Absorption into the body
- Distribution to the site of action
- Target interaction (e.g., binding to cellular receptors or ion channels)
- Metabolic processing
Variation in genes in the PK and PD drug response pathways can occur at any one of the five stages.
Gene variants in the PK drug response pathway change how the drug works by altering the level of drug concentration and its metabolites at the site of drug action. In most cases, gene variants can convert the drug to inactive metabolites and decrease the drug’s potency, essentially making the drug ineffective. Gene variants can also increase the concentration level of drug metabolites, which can make the drug more potent. Dangerous effects such as liver failure and seizures can result from the presence of too much of the drug. In addition, a drug may be converted to different metabolites that change the action of the drug and can result in unexpected effects.
On the other hand, gene variants affecting the PD pathway change the way that the drug works by altering the molecules that are targeted by the drug. Changes in genes in the PD drug response pathway can lead to differences in the functional proteins and enzymes that are encoded by the gene, consequently changing the way that the drug is processed.
Variations in genes in the PD drug response pathway can also result in changes in the molecules that are targeted by the drug. For example, variations in the genes in the PD pathway can change the ability of the drug to bind to targeted receptor proteins, essentially blocking the function of the drug.
Importance of the liver in drug metabolism
One of the main functions of the liver is to break down and process the substances we ingest. The liver is the largest gland in the body and is responsible for breaking down nutrients, storing vitamins and minerals, producing red blood cells (RBCs) and Kupffer cells to help fight infection, regulating metabolic processes and disposing of toxins. Every vitamin, over-the-counter (OTC) medication, prescription medication, and dietary and herbal supplement that a person takes passes through the liver.
Enzymes in the liver play an important role in processing drugs. Genetic variants can change the way that enzymes in the liver work, altering the person’s response to certain drugs. For example, genetic changes to the cytochrome P450 enzyme of the liver can affect the way that certain drugs such as benzodiazepines, opioid analgesics, antibiotics and antihypertensive drugs are metabolized. In addition, about half of the people in the United States have a liver enzyme called N-acetyltransferase, which causes certain drugs to be metabolized more slowly, wrote Daniel A. Hussar, Ph.D., in the Merck Manual.
Types of genetic variants in genes
The two common types of variation in genes in humans are single nucleotide polymorphisms (SNPs) and structural variations. SNPs involve genetic changes in a single nucleotide base in a person’s DNA. Structural variations, on the other hand, can be caused by insertions, deletions or duplications of small DNA segments, which can alter the structure of the entire chromosome. Unique combinations of genes are referred to as alleles. Every person inherits two copies of each gene from each of his or her biological parents. There can be many different types of combinations for each drug metabolizing gene. Pharmacogenetics uses this combination of variants in a gene to determine how an individual will respond to a drug.
Optimizing drug selection through pharmacogenetic testing
Historically, the administration of medications and dosage has relied on factors such as age, ethnicity and body weight to optimize drug selection and dosage. Unfortunately, patients vary widely in their responses to drugs. Some people experience adverse drug reactions, while others do not benefit from the drug at all. Health care providers have seen higher rates of non-response to certain medications, such as antibiotics and antidepressants. In addition, over 2 million serious adverse drug reactions result from the use of pharmaceuticals each year, contributing to more than 100,000 deaths and even more hospitalizations.
As genetic variations account for the varied responses to different psyhopharmaceuticals, including antidepressants, health care providers can use their knowledge of genetic variants for choosing certain medications for patients. There are now a total of 113 drugs with gene variants that have been approved by the U.S. Food and Drug Administration (FDA), which can be used to avoid adverse side effects, optimize drug dose and determine how a person will respond to a drug.
Sovereign Health of California offers pharmacogenetic testing for patients in treatment for substance abuse and addiction, mental illness and co-occurring disorders. Patients who receive pharmacogenetic testing receive evidence-based and individualized behavioral treatments based on their specific needs. For more information on the pharmacogenetic testing or programs offered at Sovereign Health, please contact our 24/7 helpline to speak to a member of our team.
About the author
Amanda Habermann is a writer for the Sovereign Health Group. A graduate of California Lutheran University, she received her M.S. in clinical psychology with an emphasis in psychiatric rehabilitation. She brings to the team her background in research, testing and assessment, diagnosis and recovery techniques. For more information and other inquiries about this article, contact the author at firstname.lastname@example.org.