Written by Julie Bick, Ph.D.
With the development of precision medicine protocols, genetic profiling is becoming standard-of-care in many areas of medicine. The combination of genetics and pharmacology has led to the development of pharmacogenomics—a field that explores how an individual's genetic makeup influences their response to medications. Central to this is the concept of "pharmacogenes," the genetic players that determine how our bodies absorb, metabolize, and excrete certain drugs. In this blog, we explore what pharmacogenes are, their role in drug response, and their implications for personalized medicine.
Pharmacogenes are genes that encode proteins involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs. These proteins include enzymes, transporters, and receptors that influence how a drug behaves in the body and how the body responds to the drug. Variations in these genes can lead to differences in drug efficacy and the risk of adverse effects among individuals.
The most well-studied pharmacogenes belong to families such as cytochrome P450 (CYP), ATP-binding cassette (ABC) transporters, and solute carrier (SLC) transporters. Each of these plays a unique role in drug metabolism and transport, that ultimately influences how an individual responds to a drug.
Cytochrome P450 enzymes are responsible for the metabolic breakdown of many drugs, mostly through their monooxygenase activities (Estabrook 2003). Variants in genes like CYP2D6, CYP2C19, and CYP3A4 can alter drug metabolism rates, categorizing individuals as poor, intermediate, extensive, or ultra-rapid metabolizers. There are caveats to the impact of these metabolism profiles based on whether the medication is a pro-drug or the active compound and we’ll discuss this later in the blog.
Drug Transporters such as the P-glycoprotein (encoded by ABCB1) and organic anion-transporting polypeptides (encoded by SLCO1B1) regulate the active transport of drugs across cell membranes, affecting bioavailability and distribution.
In contrast, some pharmacogenes encode the actual drug targets such as receptors or enzymes. Variants in these genes can modify drug binding and efficacy, influencing therapeutic outcomes.
Genetic variation in pharmacogenes typically arises from single nucleotide polymorphisms (SNPs), insertions, deletions, or copy number variations. These variations can impact drug response in several ways from modifying the rate at which the drug is metabolized or in cases where there is a loss-of-function variant, the drug may have no efficacy at all. The cellular membrane transport systems affect the transport and distribution of the drug throughout the body and since these are often expressed in a tissue-specific manner, this may lead to mal-absorption of the drug, or an accumulation of the drug in a particular organ or tissue; an example of this involves polymorphisms of the SLCO1B1 gene encoding the organic anion transporting polypeptide 1B1 that is mainly expressed in the liver. A variant known as SLCO1B1 T521C is associated with a higher risk of statin-induced myopathy (SIM), particularly with simvastatin, rosuvastatin and cerivastatin (Xiang et. al. 2018). SIM is a muscle disorder that can range from mild muscle pain known as myalgia, to life-threatening muscle damage known as rhabdomyolysis. It is caused by prescription statins. These are one of the most commonly prescribed medications, and around 30% of patients on statin drugs will experience some form of myopathy, therefore pre-emptive PGx testing represents an important tool to help mitigate the risk associated with these drugs.
https://www.healthline.com/health/what-is-statin-induced-myopathy-or-muscle-pain#recoveringMutations in the actual drug targets can reduce or enhance drug binding, altering therapeutic effects. One well characterized example of this involves variants in VKORC1, a gene that encodes the target of the anticoagulant drug warfarin. Warfarin has a very narrow therapeutic index therefore the dose needs to be tailored for each patient’s response in order to achieve target anticoagulation. PGx profiles for the VKORC1 gene, along with CYP2C9 are being used to optimize dosing and avoid overdosing or underdosing the patient to achieve optimal anticoagulation as soon as possible (Dean, 2018)
Genetic variants create distinct phenotypes that influence drug response based on the transport, metabolism and target sensitivity for a given drug. It should be noted that drug-gene interactions are not understood for all drugs, and there are many reported gene variants with unknown effects, but as the field of PGx continues to grow and more databases used to compile and analyze PGx profiles to support clinical decision making.
Prodrugs are drugs that are considered inactive or less active when administered to the patient and must be metabolized by the body to produce the active therapeutic compound.
Many prodrugs are activated by CYP450 enzymes, often in the liver, genetic polymorphisms in these enzymes can alter the rate of conversion of the pro-drug to the active compound. Poor metabolizers (PMs) have reduced enzyme activity and may not effectively convert the prodrug into its active form, leading to reduced efficacy.
Ultra-rapid metabolizers (UMs) have increased enzyme activity and may convert the prodrug too quickly, potentially causing toxicity.
A common example of this is the response to the prodrug codeine. Codeine is metabolized into morphine by the enzyme CYP2D6. Whereas poor metabolizers may experience inadequate pain relief, ultra-rapid metabolizers risk morphine toxicity.
Active drugs are administered in their pharmacologically active form and therefore do not require metabolic activation but are often metabolized for clearance. Genetic polymorphisms can affect how quickly or slowly the drug is metabolized and cleared from the body. In patients who are poor metabolizers, drug levels may accumulate, increasing the risk of side effects or toxicity, whereas patients who are ultra-rapid metabolizers may clear the drug too quickly, thereby reducing therapeutic efficacy.
Pharmacogenomic testing is most commonly used by clinicians to tailor drug prescriptions and dosages based on a patient’s genetic profile. This minimizes trial-and-error prescribing and reduces the likelihood of adverse drug reactions (ADRs). However, more recently, pharmacogenomic insights are also transforming drug development by identifying genetic factors that contribute to drug efficacy and toxicity. This may be used to streamline clinical trials as well as support the development of more effective therapies. As more studies are published and genetic data made available, the hope is that understanding pharmacogene variability across populations will be valuable in addressing disparities in drug response. Genetic variations often differ among ethnic groups, influencing the prevalence of specific phenotypes. For example, variants in CYP3A5 are more common in individuals of African descent, affecting the metabolism of tacrolimus, a drug used in transplant patients. This is particularly significant for kidney transplant recipients since Chronic Kidney Disease (CKD) disproportionately affects individuals of African descent in the US. The CYP3A5*1 (expressor allele) is associated with higher tacrolimus metabolism; consequently, patients may require higher drug doses (typically 1.5 to 2 times higher than the standard starting dose) to achieve therapeutic levels of the drug. In contrast, CYP3A5*3, 6, 7 (non-expressor alleles) result in non-functional or highly reduced functioning CYP3A5 enzyme and therefore these patients require lower doses of tacrolimus to avoid toxicity (Chen and Prasad, 2018).
Pharmacogenes represent a cornerstone of personalized medicine, tying genetics with pharmacology. By understanding the genetic factors that influence drug response, we can move closer to achieving safer and more effective treatments for all. As research advances and healthcare systems adapt, PGx is set to revolutionize medicine, ensuring that ‘the right drug is given at the right dose to the right patient’- a goal shared by all stakeholders in the healthcare field.
Estabrook RW (December 2003). "A passion for P450s (Remembrances of the early history of research on cytochrome P450)". Drug Metabolism and Disposition. 31 (12): 1461–1473.
Xiang, Q., Chen, Sq., Ma, Ly. et al. Association between SLCO1B1 T521C polymorphism and risk of statin-induced myopathy: a meta-analysis. Pharmacogenomics J 18, 721–729 (2018). https://doi.org/10.1038/s41397-018-0054-0
Dean L. Warfarin Therapy and VKORC1 and CYP Genotype. 2012 Mar 8 [Updated 2018 Jun 11]. In: Pratt VM, Scott SA, Pirmohamed M, et al., editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK84174/
Chen L, Prasad GVR. CYP3A5 polymorphisms in renal transplant recipients: influence on tacrolimus treatment. Pharmgenomics Pers Med. 2018 Mar 7;11:23-33. doi: 10.2147/PGPM.S107710. PMID: 29563827; PMCID: PMC5846312.
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