Pharmacogenetics: The Influence of Genetic Variants on Drug Metabolism

Driven by advances in research and the growing demand for personalized treatments, pharmacogenetics is gaining increasing prominence in clinical practice worldwide. We are entering an era of ever more precise treatments, where medications are selected based on each individual’s genetic profile, boosting therapeutic success rates and reducing the risk of adverse reactions. 

It is estimated that around 90% of patients carry genetic variants that may influence their response to medications, according to data from the FDA (Food and Drug Administration). Thus, pharmacogenetics is revolutionizing medicine, with a market expected to exceed $18 billion by 2030, according to market studies (1). 

What is pharmacogenetics?

Pharmacogenetics is the area of science that studies how individual genetic variations influence drug response (2). 

Currently, pharmacogenetics is based on the analysis of genes associated with the hepatic metabolism of drugs, highlighting the role of the cytochrome P450 superfamily, which acts in the drug metabolism pathways and performs most biotransformation reactions. Variants in these genes can alter enzyme expression, selectivity, or activity, leading to a diverse range of drug responses (3). 

Other genes related to drug pharmacokinetics and pharmacodynamics, such as receptors, transporters, and phase II enzymes, among others, are also relevant. 

By identifying these variations, it becomes possible to predict how an individual metabolizes and responds to different treatments, enabling personalized therapies. This not only increases the efficacy of medications but also minimizes the risk of adverse effects. 

The importance of pharmacogenetics lies in its ability to guide clinical decisions, making treatment safer and more effective, especially in areas like oncology, psychiatry, and chronic diseases, where treatment responses can vary widely among patients. 

Drug metabolism

Drug metabolism involves several chemical reactions that modify the molecular structure of medications to produce metabolites, which are typically less active, more water-soluble, and easier to excrete (4). 

Most medications are metabolized in the liver, where enzymes either deactivate (for already active drugs) or activate (for prodrugs) them. The primary metabolic mechanism involves cytochrome P450 enzymes. 

The hepatic metabolism of drugs involves two phases: 

• Phase I: Oxidation or reduction reactions modify the drug molecule, affecting its pharmacological activity in terms of efficacy or toxicity. These reactions in Phase I are carried out by the cytochrome P450 enzyme family;

• Phase II: Conjugation reactions make drugs or their metabolites more water-soluble to facilitate elimination.

For prodrugs, active ingredients that lack biological activity in their administered form, activation occurs only after hepatic metabolism, enabling their pharmacological effect (5). Consequently, population variants affecting enzymatic activity could prevent the formation of the active compound. 

As most drugs are metabolized by cytochrome P450 enzymes, any variation in enzyme levels directly impacts drug action. 

Various genes are involved in the expression of enzymes that metabolize drugs. Thus, pharmacogenetic studies allow us to predict drug efficacy and toxicity, enabling tailored and individualized pharmacological treatment. 

How can drug metabolism be classified?

By understanding the genes and genetic variants involved in enzyme expression, we can determine a patient’s metabolic type for a given medication. 

Analyzing genes involved in drug metabolism allows us to classify patients into five categories or phenotypes:

• Normal Metabolizer: This category includes most of the population. Individuals in this group have two active gene copies and display a normal metabolizing capacity, usually allowing them to receive the standard drug dosage. The same applies to prodrugs;

• Poor Metabolizer: This group includes individuals with two inactive copies of the gene. 

Poor metabolizers face a higher risk of adverse reactions. Since their drug metabolism rate is reduced, toxicity is increased. To avoid toxicity, these patients are generally recommended a lower drug dose or an alternative treatment. 

For prodrugs, poor metabolizers have a lower conversion rate to the active drug, resulting in fewer adverse effects and a lower likelihood of achieving adequate therapeutic response. Therefore, for prodrugs, a higher dose is usually recommended, though the maximum dose should not be exceeded; 

• Intermediate Metabolizer: Intermediate metabolizers generally have one inactive gene copy or two partially active copies, resulting in a metabolism rate lower than normal, which can lead to drug accumulation and an increased risk of adverse toxic events. 

To prevent possible toxic effects, a reduced drug dose is recommended, as this may also lower therapeutic response. Alternatively, the standard dose can be administered with caution for potential toxic events. 

For prodrugs, intermediate metabolizers have a lower conversion rate from prodrug to active drug, reducing adverse effects and the likelihood of an adequate therapeutic response. In these cases, a higher dose is recommended, but the maximum dose should not be exceeded. The dose increase should be smaller than for poor metabolizers; 

• Rapid Metabolizer: This group usually has a higher number of active gene copies due to gene duplication, resulting in a metabolism rate higher than standard. 

For medications, these individuals may experience lower toxicity but also a reduced therapeutic effect due to faster drug clearance. A higher drug dose is recommended in these cases. 

For prodrugs, the conversion to active drug is faster, increasing the risk of adverse effects due to higher exposure. A lower dose is recommended for prodrugs in this group; 

• Ultrarapid Metabolizer: This group also has more active gene copies from gene duplication, with a metabolism rate even higher than that of rapid metabolizers. 

For medications, ultrarapid metabolizers may have lower toxicity and reduced therapeutic effect due to significantly faster drug clearance. Switching to an alternative drug with a more effective therapeutic action is advised. 

For prodrugs, the conversion to active drug occurs even more rapidly than in rapid metabolizers, increasing the risk of adverse effects. Switching to a drug with a lower toxicity profile is also recommended in these cases. 

What are pharmacogenetic tests?

Pharmacogenetic tests assess how the body metabolizes and reacts to specific medications by identifying genetic variations that influence this metabolism. Based on these findings, doctors can anticipate responses to treatments and select the most appropriate medications and dosages for each patient. 

These tests are fundamental in personalized medicine, aiming to minimize side effects and maximize treatment effectiveness, especially for drugs like antidepressants, antipsychotics, and oncology drugs. 

What is a pharmacogenetic panel?

A pharmacogenetic panel is a comprehensive analysis that investigates an individual’s ability to metabolize a variety of medications. It examines genetic variations in genes that affect drug absorption, transport, and elimination, offering a complete view for treatment personalization. 

The panel covers different classes of medications, such as antidepressants and anticonvulsants, facilitating the selection of the most effective and safe therapeutic options while reducing the risk of adverse reactions. 

SYNLAB’s pharmacogenetic panel 

SYNLAB’s PGx GLOBAL pharmacogenetic panel evaluates variants in genes responsible for the expression of key enzymes involved in the metabolism of commonly used drugs across various therapeutic areas. 

The analysis provides relevant information about 161 of the most commonly used drugs, based on the study of 55 genetic variants documented in scientific literature, present in 13 genes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A5, ABCB1, COMT, FACTOR II, FACTOR V, MTHFR, SLCO1B1 and VKORC1. 

Which medications are analyzed in the Global PGx?

The panel analyzes 161 medications from the following categories: 

• ANALGESICS AND ANTI-INFLAMMATORIES: Aceclofenac, Alfentanil, Buprenorphine, Celecoxib, Codeine, Diclofenac, Fentanyl, Hydrocodone, Ibuprofen, Indomethacin, Meloxicam, Naproxen, Oxycodone, Piroxicam, Propoxyphene, Sufentanil, Tramadol;
• ANTIBIOTICS: Clarithromycin, Clindamycin, Doxycycline, Erythromycin, Trimethoprim;
• ANTIMETICS: Aprepitant, Granisetron, Metoclopramide, Nabilone, Ondansetron, Promethazine, Tropisetron;
• ANTIMIGRAINES: Eletriptan;
• ANTIEPILEPTICS: Carbamazepine, Ethosuximide, Phenytoin, Phenobarbital, Zonisamide;
• ANTIFOLATES: Methotrexate;
• ANTIFUNGALS: Itraconazole, Ketoconazole, Voriconazole;
• RESPIRATORY: Chlorpheniramine, Diphenhydramine, Fluticasone, Loratadine, Meclizine, Salmeterol;
• ANTICOAGULANTS AND ANTIPLATELET AGENTS: Acenocoumarol, Acetylsalicylic Acid, Apixaban, Clopidogrel, Dabigatran, Edoxaban, Phenprocoumon, Rivaroxaban, Ticagrelor, Warfarin;
• ANTIDEPRESSANTS: Amitriptyline, Citalopram, Clomipramine, Desipramine, Doxepin, Duloxetine, Escitalopram, Fluvoxamine, Imipramine, Mirtazapine, Moclobemide, Nortriptyline, Paroxetine, Reboxetine, Sertraline, Trazodone, Venlafaxine;
• ANTIHYPERTENSIVES: Amlodipine, Barnidipine, Betaxolol, Bisoprolol, Captopril, Carvedilol, Celiprolol, Diltiazem, Doxazosin, Enalapril, Felodipine, Irbesartan, Lercanidipine, Losartan, Metoprolol, Nebivolol, Nicardipine, Nifedipine, Nimodipine, Nisoldipine, Nitrendipine, Propranolol, Terazosin, Triamterene, Valsartan, Verapamil;
• ANTIPSYCHOTICS: Aripiprazole, Asenapine, Clozapine, Olanzapine, Quetiapine, Risperidone;
• ANXIOLYTICS: Alprazolam, Bromazepam, Buspirone, Clobazam, Clonazepam, Chlordiazepoxide, Diazepam, Flurazepam, Ketazolam, Triazolam;
• CARDIOVASCULAR: Amiodarone, Digoxin, Disopyramide, Dronedarone, Flecainide, Lidocaine, Procainamide, Propafenone, Quinidine;
• DIURETICS: Spironolactone, Torsemide;
• DIABETES: HYPOGLYCEMICS: Glibenclamide, Glimepiride, Glipizide;
• STATINS – HYPOLIPEMICS: Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin;
• GLUCOCORTICOIDS: Budesonide, Prednisone;
• HYPNOTICS AND SEDATIVES: Amobarbital, Brotizolam, Hydroxyzine, Melatonin, Zolpidem, Zopiclone;
• HORMONALS: Estradiol, Ethinyl Estradiol, Medroxyprogesterone, Progesterone;
• PROTON PUMP INHIBITORS: Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole;
• PARKINSON AND ALZHEIMER: Donepezil, Levodopa, Ropinirole;
• PSYCHOANALYTICS: Atomoxetine;
• MUSCLE RELAXANTS: Cyclobenzaprine, Tizanidine;
• GENITOURINARY SYSTEM AND SEXUAL HORMONES: Oxybutynin, Tamsulosin;
• GOUT TREATMENT: Colchicine.

Who is the Global PGx test recommended for?

The SYNLAB Global PGx pharmacogenetic test is recommended for: 

• Patients undergoing pharmacological treatment who wish to personalize their medication based on their genetic profile;
• Patients on multiple medications;
• Patients experiencing drug side effects;
• Patients in whom pharmacological treatments have not yielded expected results;
• Patients initiating drug therapy, especially in chronic treatments;
• Patients with a family history of adverse drug reactions.

What methodology is used in the test? 

SYNLAB’s Global PGx test uses the MassARRAY technique, a mass spectrometry-based platform that allows rapid and efficient analysis of genetic variations, including single nucleotide variants (SNVs), insertions, deletions, and mutations. 

MassARRAY employs a unique approach, where DNA amplification is combined with mass spectrometry detection. DNA is amplified by PCR, and instead of detecting PCR products directly, the amplified fragments undergo allele-specific extension, followed by ionization and mass spectrometry analysis to determine the molecular weight of each variant. 

What Benefits Can the Global PGx Test Offer?

Numerous genes responsible for enzyme expression in drug metabolic pathways have genetic variants that cause changes in enzyme expression, selectivity, or activity, reflecting the diversity of drug responses. 

Through analysis of variants in genes involved in the expression of drug-metabolizing enzymes, it is possible to classify the metabolism of each drug analyzed, aiming to assist prescribers in providing more effective and individualized treatment for patients. 

What Other Pharmacogenetic Tests Does SYNLAB Offer? 

SYNLAB offers a wide range of pharmacogenetic tests categorized as follows: 

• FG Cardio Complete: Studies the major metabolizing enzymes and targets involved in the effect and toxicity of the 52 most commonly used drugs for cardiovascular disease treatment;

• FG Onco Lapatinib: Studies the presence of HLA DQA102:01 and DRB107:01 alleles to identify an increased probability of serious side effects, particularly hepatotoxicity, with Lapatinib treatment;

• NEURO PGx Gene Panel: Provides relevant information on 81 commonly used drugs for the treatment of neurological and psychiatric conditions, such as depression, anxiety, schizophrenia, and bipolar disorder, based on the study of 50 genetic variants in genes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, CYP2B6 and ABCB1.

Discover the SYNLAB Group, a Leader in Medical Diagnostic Services! 

The precision and accuracy of diagnostic tests are essential for better diagnoses and for guiding treatments. SYNLAB is here to help. 

We offer diagnostic solutions with rigorous quality control to companies, patients, and doctors. Operating in Brazil for over 10 years, we are active in 36 countries across three continents and are the leading diagnostic services provider in Europe. 

Get in touch with the SYNLAB team and explore the available tests. 

References 

1) Data Bridge Market Research. (2023). Pharmacogenomics Market Size, Share & Growth Report | 2031. Available at:  www.databridgemarketresearch.com/reports/global-pharmacogenomics-market 

2) Meyer UA. Pharmacogenetics – five decades of therapeutic lessons from genetic diversity. Nat Rev Genet. 2004 Sep;5(9):669-76.  

3) Lu DY. Personalized Cancer Chemotherapy. Pharmacogenetics.  2015; 21–28. doi:10.1016/b978-0-08-100346-6.00004-2  

4) Metabolismo dos medicamentos – Medicamentos – Manual MSD Versão Saúde para a Família (msdmanuals.com)  

5) ChungI MC, Silva ATA, CastroI LF, Güido RVC, NassuteI JC, Ferreira EI. Latentiation and advanced drug transport forms. Rev. Bras. Cienc. Farm. 2005;41(2).