Pharmacogenetics: Influence of genetic variants on drug metabolism

What is pharmacogenetics? 

Several genes are responsible for the expression of cytochrome P450 enzymes that act in the metabolism pathways of drugs. Thus, variants in these genes can alter the expression, selectivity or activity of the enzyme, reflecting a diversified response to drugs.  

Pharmacogenetics refers to the influence of genes on the individual response to drugs. 

Drug metabolism 

The metabolism of a drug consists of several chemical reactions of the drug in the body, which modify it and, in general, convert it into a more soluble molecule that can be excreted more easily.   

In the case of prodrugs, which are drugs administered      inactive, their activation occurs only after metabolization, and thus it is possible to achieve their pharmacological effect.  

Most drugs have their metabolism in the liver, where enzymes that will inactivate (in the case of already active drugs) or activate (in the case of prodrugs) act. The main metabolization mechanism is carried out by cytochrome P450 enzymes.  

As most drugs are metabolized by cytochrome P450 enzymes, any change in the concentration of these enzymes will directly affect the action of the drugs. 

Different genes are involved in the expression of enzymes that act in the metabolism of drugs. Therefore, through pharmacogenetic studies it is possible to predict the efficacy and toxicity of the medication, making it possible to target and customize the pharmacological treatment. 

How can metabolism be classified? 

With the knowledge of the genes, as well as the genetic variants, involved in the expression of the metabolizing enzymes, it is possible to determine the type of metabolism of a patient when facing a drug product.  

The analysis of the genes involved in the metabolism of drug products allows the distinction of 5 categories or phenotypes: 

•  Normal Metabolizers: They comprise the majority of the population. Represented by individuals who have two active copies of the gene.  

Individuals in this group have a normal metabolizing capacity and, in general, can receive the drug dose established as standard. The same is true for prodrugs. 

• Slow Metabolizers: Include individuals who have both copies of the gene inactive.  

This class of metabolizers represents a greater risk of possible adverse reactions. As in these cases the rate of drug metabolism is reduced from drug metabolism, it presents greater toxicity. In order to avoid toxicity, it is generally recommended that, for these patients, the dose of the drug product is reduced or that the treatment be carried out with another drug product.   

For prodrugs, patients with slow metabolism have a lower rate of conversion of prodrug to active drug. Thus, there is a decrease in the probability of adverse effects, in addition to a lesser probability of an adequate therapeutic response.  

Therefore, in the case of prodrugs, a higher dose of the drug is generally recommended, but the maximum dose should not be exceeded.  

• Intermediate metabolizers: Intermediary metabolizers usually have one inactive copy of the gene or two partially active copies. This implies that the drug’s metabolism is lower than normal and, therefore, can accumulate in the body resulting in an increased risk of adverse toxic events. 

In order to avoid the possible emergence of these adverse toxic events, it is recommended to use a reduced dose of the drug, considering that this can also decrease the therapeutic response or the standard dose of the drug, with attention to the possible emergence of adverse toxic events. 

For prodrugs, patients with intermediate metabolism have a lower conversion rate between prodrug and active drug, resulting in a lesser probability of adverse effects. However, it also results in a lower rate of adequate therapeutic response. In such cases, it is recommended to administer a higher dose, not exceeding the maximum recommended dose. The dose increase should be less than in the case of an individual with slow metabolism. 

• Fast Metabolizers: This group, in general, has a higher number of active copies of the gene, resulting from the duplication of this gene. As a result, they have a metabolic rate higher than standard.  

In relation to drugs, these individuals may have less toxicity, but they also have a lower therapeutic index, due to the increase in the elimination of drugs. In these cases, an increase in the dose of the drug is recommended.  

Conversely, for prodrugs, the conversion to an active drug is faster, thus presenting a greater risk of adverse effects due to the increase in the exposure of the drug. For prodrug cases, a lower dosage of the drug product is recommended. 

• Ultra-fast metabolizers: This group also has a higher number of active copies of the gene, as a result of gene duplication, presenting a metabolic rate higher than standard and, in this case, higher than that of fast metabolizers.  

In relation to the drug products, these individuals may have less toxicity, but they also have a lower therapeutic index, due to the increase in the elimination of drugs, even greater than in fast metabolizers. In these cases, it is recommended to change the drug product to another one in which the therapeutic action is greater.  

Conversely, for prodrugs, the conversion to active drugs is faster, thus presenting a greater risk of adverse effects due to the increased exposure of the drug, even greater than in fast metabolizers. For these cases, it is also recommended to change the drug product to another one in which the toxicity is lower.   

FG Basic 

The FG – Basic pharmacogenetic panel offered by SYNLAB assesses variants in the genes responsible for the expression of the main enzymes involved in the metabolism of the drugs most commonly used in different therapeutic areas, from a single blood collection.  

What drug products are analyzed in FG-Basic? 

188 drug products and 22 variants are analyzed in genes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5, of the following classes: 

• Allergies and respiratory system: Tiotropium bromide, Budesonide, Chlorphenamine, Diphenhydramine, Fluticasone, Ipratropium, Loratadine, Montelukast, Salbutamol, Salmeterol. 

• Alzheimer, Parkinson and ADHD: Atomoxetine, Donepezil, Galantamine, Levodopa, Methylphenidate, Rivastigmine, Ropinirole and Seleginine.  

• Painkillers: Aceclofenac, Buprenorphine, Celocoxib, Codeine, Diclofenac, Etodolac, Fentanyl, Hydrocodone, Hydromorphone, Ibuprofen, Indomethacin, Meloxicam, Meperidine, Methadone, Naproxen, Oxycodone, Acetaminophen, Piroxicam, Propoxyphene, and Tramadol.  

• Anxiolytics: Alprazolam, Bromazepam, Clobazam, Clonazepam, Clorazepate, Chlordiazepoxide, Diazepam, Doxepin, Flunitrazepam, Flurazepam, Halazepam, Estalozam, Methadone, Naltrexone, Quazepam, Triazolam, Zolpidem, and Zopiclone.  
• Antibiotics: Amoxicillin, Azithromycin, Clarithromycin, Clindamycin, Doxycycline, Erythromycin, and Sulfamethoxazole.  

• Anticoagulants and antiarrhythmics: Acetyl-salicylic acid (ASA), Acenocoumarol, Amiodarone, Clopidogrel, and Warfarin.  

• Antidepressants: Amitriptyline, Bupropion, Citalopram, Clomipramine, Duloxetine, Escitalopram, Fluoxetine, Fluvoxamine, Imipramine, Mirtazapine, Moclobemide, Nortriptyline, Paroxetine, Reboxetine, Sertraline, and Venlafaxine.  

• Antiepileptic drugs: Valproic Acid, Carbamazepine, Clobazam, Clonazepam, Ethosuximide, Phenytoin, Phenobarbital, Oxcarbazepine, and Zonisamide.  

• Antihypertensive drugs: Amlodipine, Barnidipine, Betaxolol, Bisoprolol, Candesartan, Captopril, Carvedilol, Celiprolol, Diltiazem, Doxazosin, Enalapril, Felodipine, Irbesartan, Labetalol, Lercanidipine, Losartan, Manidipine, Metoprolol, Nebivolol, Nicardipine, Nifedipine, Nimodipine, Nisoldipine, Nitrendipine, Propranolol, Terazosin, Timolol, Torsemide, Triamterene, Valsartan, and Verapamil.  

• Antimigraine drugs: Almotriptan, Eletriptan, Rizatriptan, and Zolmitriptan.  

• Antineoplastic drugs: AQ4N, Cyclophosphamide, Dacarbazine, Docetaxel, Doxorubicin, Ellipticine, Etoposide, Ifosfamide, Imatinib, Irinotecan, Mitoxantrone, Paclitaxel, Tamoxifen, Teniposide, Thiotepa, Topotecan, Vinblastine, Vincristine, Vindesine, and Vinorelbine.  

• Antipsychotics: Aripiprazole, Clozapine, Fluphenazine, Haloperidol, Levomepromazine, Olanzapine, Perphenazine, Pimozide, Quetiapine, Risperidone, Sertindol, Trifluoperazine, Vortioxetine, Ziprasidone, and Zuclopenthixol.  

• Antidiabetics and Cholesterol: Atorvastatin, Fenofibrate, Fluvastatin, Gemfibrozil, Glibenclamide, Glimepiride, Glipizide, Lovastatin, Repaglinide, and Simvastatin.  

• Steroids: Ethinyl Estradiol, Medroxyprogesterone, and Progesterone.  

• Gastroenterology and Urology: Esomeprazole, Famotidine, Lansoprazole, Metoclopramide, Omeprazole, Pantoprazole, Rabeprazole, Sildenafil, Tadalafil, and Tamsulosin. 

Who is the exam indicated for? 

The SYNLAB FG Basic exam is indicated for: 

• Patients undergoing pharmacological treatment who wish to personalize their medication based on their genetic profile.
• Polymedicated patients.
• Patients with side effects to the drugs.
• Patients in whom pharmacological treatments do not provide the expected results.
• Patients who are going to start drug treatments, especially if the treatment is chronic.
• Family history of adverse drug reactions.

What is the methodology used in the test? 

SYNLAB FG Basic exam is performed by Next Generation Sequencing (NGS).  

The used methodology allows greater agility of the process, high throughput and greater sensitivity of the analysis, the latter being 99%.  

What benefits can the FG – Basic test offer? 

Through the analysis of the variants in genes involved in the expression of the metabolizing enzymes of the drug products, it is possible to classify the metabolism for each analyzed drug, with the objective of assisting the prescribing physician in a more effective and individualized treatment for the patient.  

Other pharmacogenetics testing offered by SYNLAB 

SYNLAB has a wide availability of pharmacogenetic testing that can be distributed in the following categories: 

• Pharmacogenetics of neurological disorders: 

– FG Neuro Depression:  It studies the main metabolizing enzymes and targets that are implicated in the effect and toxicity of the 15 most used drugs for the treatment of anxiety. 

– FG Neuro Anxiety: It studies the main metabolizing enzymes and targets that are implicated in the effect and toxicity of the 13 most used drugs for the treatment of anxiety.  

– FG Neuro Psychosis: It studies the main metabolizing enzymes and targets that are implicated in the effect and toxicity of the 14 most used drugs for the treatment of psychosis.  

– FG Neuro Epilepsy:  It studies the main metabolizing enzymes and targets that are implicated in the effect and toxicity of the 11 most used drugs for the treatment of epilepsy. 

• Pharmacogenetics for cardiovascular diseases 

– FG Cardio Arrhythmia: It studies the main metabolizing enzymes and targets that are implicated in the effect and toxicity of the 5 most used drugs for the treatment of arrhythmia.  

– FG Cardio Hypertension: It studies the main metabolizing enzymes and targets that are implicated in the effect and toxicity of the 33 most used drugs for the treatment of hypertension.  

– FG Cardio Vascular: It studies the main metabolizing enzymes and targets that are implicated in the effect and toxicity of the 14 most used drugs for the treatment of cardiovascular diseases.  

– FG Cardio Complete: It studies the main metabolizing enzymes and targets that are implicated in the effect and toxicity of the 52 most used drugs for the treatment of cardiovascular diseases. 

• Pharmacogenetics for oncology 

– FG Onco 5-Fluorouracil: It studies the main variants in the DPYD and TYMS genes in order to identify an increase in the likelihood of serious side effects to treatment with 5-Fluoracil (Capecitabine). 

– FG Onco Cisplatin: It studies the main variants in the TPMT gene, which are associated with more than 95% in reducing the activity of the TPMT enzyme. The study aims to identify patients with decreased activity of the TPMT enzyme and, therefore, an increase in the likelihood of serious side effects to treatment with Cisplatin. 

– FG Onco Irinotecan: It studies the main variants in the UGT1A1 gene in order to identify the effective response or an increase in the likelihood of serious side effects to treatment with Irinotecan.  

– FG Onco Lapatinib: Is studies the presence of the HLA DQA1*02:01 and DRB1*07:01 alleles in order to identify an increase in the likelihood of serious side effects, especially hepatotoxicity, to treatment with Lapatinib.  

– FG Onco Methotrexate: It studies the main variants in the MTHFR gene, which are associated with more than 95% in the reduction of enzymatic activity. The study aims to identify patients with decreased activity of the MTHFR enzyme and, therefore, an increase in the likelihood of serious side effects to treatment with Methotrexate. 

– FG Onco Tamoxifen: It studies the main variants in the CYP2D6 gene. The study aims to identify patients, an increase in the likelihood of serious side effects and less efficacy to treatment with Tamoxifen.  

– FG Onco Thiopurines: It studies the main variants in the TPMT gene, which are associated with more than 95% in reducing the activity of the TPMT enzyme. The study aims to identify patients with decreased activity of the TPMT enzyme and, therefore, an increase in the likelihood of serious side effects to treatment with Thiopurines. 

About the SYNLAB Group 

The SYNLAB Group is a leader in providing medical diagnostic services in Europe, providing a full range of clinical laboratory analysis services to patients, healthcare professionals, clinics and the pharmaceutical industry. Resulting from the Labco and SYNLAB merger, the new SYNLAB Group is the undisputed European leader in medical laboratory services.