The effectiveness and side effects of drugs vary from person to person, and genetic factors are one of the reasons for this. By utilizing genetic testing, it will be possible to select drugs and adjust dosages appropriate for each patient, which will lead to effective and safe treatment.
1. The Importance of Genetic Testing
Genetic testing can identify genetic polymorphisms in drug-metabolizing enzymes and drug transporters, and predict the effectiveness of drugs and the risk of side effects. This is helping to make personalized medicine a reality.
2. Drug-metabolizing enzymes and genetic polymorphisms
Genetic polymorphisms of drug-metabolizing enzymes affect the metabolic rate, efficacy, and side effects of drugs. For example, polymorphisms in the CYP1A2 gene may change the metabolic activity of the antipyretic analgesic phenacetin, increasing the risk of side effects.
3. Clinical Applications of Genetic Testing
Genetic testing is used to predict the effectiveness and side effects of drugs. For example, by evaluating the risk of side effects of anti-cancer drugs in advance and setting appropriate dosages, safe treatment can be achieved.
4. The spread of genetic testing and its challenges
With the spread of genetic testing, treatments that take into account individual differences in drug effects and side effects are progressing. However, there are also ethical issues regarding the interpretation of test results, and careful handling is required.
Genetic testing plays an important role in predicting drug efficacy and side effects. With future research and technological advances, we can expect to see more precise personalized medicine.
Genetic testing and drug metabolism: advancing personalized medicine
The behavior of drugs in the body is determined mainly through the processes of “absorption,” “distribution,” “metabolism,” and “excretion” (ADME). Various enzymes and transporters are involved in these processes, and their functions are greatly influenced by genetic factors.
1. CYP450 enzymes and drug metabolism
The liver contains cytochrome P450 (CYP450), a group of enzymes responsible for the metabolism of many drugs. In particular, genetic polymorphisms of CYP450 determine the rate at which drugs are metabolized and greatly affect the success or failure of treatment.
a. CYP2D6 gene and antidepressants/analgesics
CYP2D6 is responsible for the metabolism of many drugs, including antidepressants (SSRIs and tricyclic antidepressants), beta-blockers, and analgesics (codeine and tramadol). There are several polymorphisms in this gene, and they are classified into the following four types depending on the metabolic rate.
Ultra-rapid metabolizer (UM) – A person who metabolizes drugs more quickly than normal and may not get the full effect they need.
Extensive metabolizer (EM) – Has general metabolic ability.
Intermediate metabolizer (IM) – Has a somewhat slow metabolic capacity.
Poor metabolizer (PM) – Metabolizes the drug very slowly and is at high risk of side effects due to drug accumulation.
For example, codeine exerts its analgesic effect by being converted to morphine by CYP2D6, but people who are ultra-rapid metabolizers produce too much morphine, increasing the risk of side effects (respiratory depression and addiction), so dosage adjustment is required.
b. CYP2C19 and antiplatelet agents/antidepressants
CYP2C19 is involved in the metabolism of **clopidogrel (antiplatelet drug) and escitalopram (antidepressant).** Clopidogrel is a drug used to prevent myocardial infarction and cerebral infarction, but it has been reported that in patients with low metabolism of CYP2C19, the drug is not activated sufficiently, resulting in a reduced antithrombotic effect.
Therefore, in poor metabolizers (PM) patients, switching to an alternative medication (e.g., prasugrel or ticagrelor) may be recommended.
How drugs are distributed in the body and reach their targets depends on the action of molecules called drug transporters.
a. ABCB1 gene and P-glycoprotein (P-gp)
P-glycoprotein (P-gp) is a transporter that exists on the cell membrane and excretes drugs from cells. It is known that polymorphisms in this gene can significantly affect the concentration of drugs in the body.
For example, because P-gp promotes the excretion of anticancer drugs and HIV drugs (protease inhibitors), people with a high-functioning type of gene are said to be more susceptible to reduced drug efficacy, while people with a low-functioning type may experience drug accumulation and an increased risk of side effects.
Statins (cholesterol-lowering drugs) are widely used to prevent cardiovascular disease, but they are known to increase the risk of muscle damage (rhabdomyolysis) in some patients. The SLCO1B1 gene is involved in this risk.
SLCO1B1 is a transporter responsible for the uptake of drugs into liver cells, and people with certain mutations in this gene have elevated blood concentrations of statins and are more likely to experience side effects. Therefore, it is recommended that patients with risk types of SLCO1B1 be treated with low-dose statins or other lipid disorder medications (such as ezetimibe) .
3. Clinical application of genetic testing and future challenges
a. Introduction of genetic testing in medical settings
Currently, **pharmacogenomics** is being introduced in many medical institutions to improve the accuracy of drug selection for specific diseases. In particular, in cancer treatment, it is now possible to determine the suitability of molecular targeted drugs by identifying gene mutations.
For example, it is known that EGFR inhibitors (gefitinib, erlotinib) are effective for lung cancer patients with EGFR gene mutations . Thus, genetic testing has become an essential tool for individualizing cancer treatment.
b. Cost and coverage challenges
However, the cost of genetic testing and issues with insurance coverage are preventing its widespread use. In Japan, some genetic tests are covered by insurance, but genetic testing is not available for all drugs.
Furthermore, ethical issues must be considered in terms of handling genetic information and protecting privacy. In particular, appropriate legislation is required to ensure that the results of genetic testing do not affect life insurance or employment.
It is expected that as technology advances, the cost of genetic testing will decrease, making personalized medicine available to more patients.
Genetic testing and risk management of side effects from drugs
Genetic testing has become an important means of predicting drug side effects in advance and prescribing appropriate medications for each patient. In particular, identifying gene polymorphisms involved in drug metabolism and immune response can reduce the risk of side effects.
1. Genes and side effects of anti-cancer drugs
While anti-cancer drugs are highly effective, they have the problem of causing strong side effects. By utilizing genetic testing, it is possible to reduce the risk of side effects and provide safer treatment.
a. DPYD gene and fluoropyrimidine anticancer drugs (5-FU, capecitabine)
Fluoropyrimidine anticancer drugs (5-FU and capecitabine) are widely used to treat colorectal and breast cancer, but some patients may experience severe side effects (such as bone marrow suppression, gastrointestinal disorders, and neuropathy) due to mutations in the DPYD gene , which is involved in the metabolism of these drugs.
In patients with DPYD gene mutations, the drug’s ability to break down is reduced, leading to accumulation in the body, so it is recommended that lower doses be administered than usual. In particular, it is recommended that 5-FU be avoided in patients with DPYD*2A mutations.
Irinotecan is an anticancer drug used to treat solid cancers, mainly colorectal cancer. This drug is metabolized by the enzyme encoded by the UGT1A1 gene , but it has been found that patients with UGT1A1 28 or UGT1A1 6 polymorphisms have a reduced metabolic capacity and an increased risk of bone marrow suppression and severe diarrhea.
For this reason, it is recommended that UGT1A1 genetic testing be performed and that patients with risk types be considered for dose reduction or alternative treatment.
In recent years, cancer immunotherapy has developed and **immune checkpoint inhibitors (ICIs)** are now widely used. However, these drugs activate the immune system and can cause side effects similar to those of autoimmune diseases (immune-related adverse events: irAEs).
a. HLA genes and side effects of immune checkpoint inhibitors
HLA (human leukocyte antigen) genes are involved in the function of the immune system, and it has been reported that people with certain HLA types are at higher risk of side effects from ICIs. For example, patients with the HLA-DRB1*04:05 genotype are said to be more likely to develop autoimmune disease-like side effects from ICIs.
Therefore, by analyzing HLA genes in advance, it is possible to identify patients at high risk of side effects and develop careful administration plans.
It is known that the effectiveness and side effects of anesthetics used during surgery are also influenced by genetic factors. In particular, genetic sensitivity to inhaled anesthetics and muscle relaxants is directly linked to patient safety, so prior genetic testing is effective.
a. RYR1 gene and malignant hyperthermia
Malignant hyperthermia (MH) is a severe adverse event that occurs in response to volatile anesthetics (e.g., sevoflurane, isoflurane) and muscle relaxants (suxamethonium). Mutations in the RYR1 gene can lead to abnormal calcium regulation, resulting in muscle rigidity, hyperthermia, and metabolic acidosis.
In patients at risk for MH, surgery can be performed safely by avoiding these agents or using alternative anesthetic agents (e.g., propofol).
The muscle relaxant suxamethonium is used to provide short-term muscle relaxation, but in some patients it can cause abnormally long-lasting paralysis due to a polymorphism in the butyrylcholinesterase (BCHE) gene.
Mutations in the BCHE gene can reduce the ability of the body to break down suxamethonium, making it difficult for patients to wake up from anesthesia. By conducting a BCHE gene test in advance, we can select the appropriate anesthetic and ensure a safe operation.
4. Genetic testing and its application in psychiatry
In the field of psychiatry, it is known that the effectiveness of antipsychotics and antidepressants varies greatly depending on the individual. By utilizing genetic testing, it becomes possible to select the most appropriate medication for each patient and minimize side effects.
For example, the HTR2A gene influences the effectiveness of antipsychotic drugs, and people with certain polymorphisms are known to be more susceptible to side effects of the drugs (such as weight gain and risk of diabetes).
In addition, variants in the COMT gene can change the rate at which dopamine is broken down, potentially affecting the effectiveness of medications for schizophrenia, so prescriptions must take genetic information into account.
Advances in genetic testing have improved drug safety and enabled more precise treatment, and it is expected that genetic testing will become standard for even more drugs in the future.
Genetic testing and the effects and side effects of antibiotics
Antibiotics are essential for treating bacterial infections, but the effectiveness and side effects of drugs vary from person to person, and it is known that genetic background is a factor in this. Utilizing genetic testing will enable safer and more effective use of antibiotics.
1. Aminoglycoside antibiotics and genetic polymorphisms
Aminoglycoside antibiotics (e.g., streptomycin, gentamicin, and amikacin) exert their bactericidal effect by targeting bacterial ribosomes, but these drugs have a significant side effect of causing hearing loss , which is genetically contributory.
a. MT-RNR1 gene and aminoglycoside-induced hearing loss
It has been reported that people with mutations in the MT-RNR1 gene in mitochondrial DNA (especially the m.1555A>G mutation) are hypersensitive to aminoglycoside antibiotics and are at high risk of developing sudden sensorineural hearing loss even with normal doses.
For this reason, if a genetic test confirms an MT-RNR1 mutation, it is recommended that the use of aminoglycosides be avoided and a different antibiotic (cephalosporin or fluoroquinolone) be selected.
2. Fluoroquinolone antibiotics and risk of tendon rupture
Fluoroquinolone antibiotics (levofloxacin, ciprofloxacin, etc.) are effective against a wide range of bacteria, but they have been known to carry the risk of tendon rupture as a side effect.
a. MMP3 gene and risk of tendon disorders
The MMP3 (matrix metalloproteinase 3) gene is involved in remodeling connective tissues in tendons and ligaments. Individuals with certain polymorphisms in this gene have been suggested to be at increased risk of tendonitis and tendon rupture when using fluoroquinolone antibiotics.
This risk is particularly increased in elderly patients and patients taking steroids concomitantly, so prior evaluation through genetic testing is considered effective.
β-lactam antibiotics (e.g. penicillin, cephalosporin) exert their bactericidal effect by inhibiting cell wall synthesis, but they can cause allergic reactions (anaphylaxis) in some patients.
a. HLA genes and penicillin allergy
Certain variants of HLA (human leukocyte antigen) genes are known to increase the risk of drug allergies. For example, it has been reported that patients with HLA-B*55:01 are at higher risk of allergic reactions to penicillin antibiotics.
For such patients, conducting genetic testing in advance would enable us to select alternative drugs and provide safe treatment.
Genetic testing and the effects and side effects of painkillers
The effects and side effects of analgesics vary from person to person, and it is known that genetic polymorphisms affect drug metabolism and the risk of dependence, particularly in the case of opioid analgesics.
1. Opioid analgesics and the CYP2D6 gene
Polymorphisms in the CYP2D6 gene are involved in the metabolism of opioid analgesics such as codeine and tramadol.
In patients who are **extremely rapid metabolizers (UMs)**, the drug is rapidly converted to morphine, increasing the risk of respiratory depression.
In patients who are **poor metabolizers (PMs)**, the medication is less effective and has reduced analgesic effects.
Therefore, genetic testing can help select appropriate painkillers and adjust dosages.
2. Nonsteroidal anti-inflammatory drugs (NSAIDs) and the risk of side effects
NSAIDs (e.g., ibuprofen, naproxen) are widely used to reduce inflammation and pain but are associated with gastrointestinal and cardiovascular risks.
a. CYP2C9 gene and metabolism of NSAIDs
The CYP2C9 gene is involved in the metabolism of NSAIDs, and it is known that patients with certain polymorphisms have a slower breakdown of the drug and an increased risk of side effects.
Individuals with the CYP2C9*2/*3 mutation may have reduced drug clearance and an increased risk of gastrointestinal bleeding and renal impairment.
For this reason, genetic testing is recommended to assess risk and develop an appropriate dosing plan.
Acetaminophen (paracetamol) is a relatively safe painkiller, but in high doses there is a risk of liver damage.
a. NAT2 gene and hepatotoxicity
Polymorphisms in the NAT2 gene affect the ability to metabolize acetaminophen, and poor metabolizers are known to be at increased risk of liver damage.
For this reason, genetic testing for NAT2 and recommending lower doses for patients with poor metabolism can lead to safe prescriptions.
Advances in genetic testing are enabling us to understand individual differences in drug effects and side effects, enabling more precise treatment. It is expected that appropriate drug selection and dosage adjustments will improve the safety and effectiveness of medical care.
Genetic testing and the effects and side effects of antipsychotics
Antipsychotic drugs are widely used to treat conditions such as schizophrenia and bipolar disorder, but their effectiveness and side effects vary greatly from person to person, and it has become clear that genetic factors are involved.
1. Dopamine receptor genes and the effects of antipsychotics
The main mechanism of action of antipsychotics is by blocking dopamine D2 receptors. Polymorphisms in the DRD2 gene, which encodes the dopamine receptor, affect the therapeutic efficacy and risk of side effects of drugs.
Patients with the TaqIA A1 allele of DRD2 have a lower density of dopamine receptors and may be attenuated in response to antipsychotics.
Patients with the A2 allele are believed to be more susceptible to the effects of the drug.
Based on this information, it will be possible to select more appropriate medications and adjust dosages.
Some antipsychotics (especially atypical antipsychotics) also act on serotonin receptors (HTR2A, HTR2C). For this reason, it is known that polymorphisms in the serotonin receptor gene affect the occurrence of side effects.
Patients with certain polymorphisms in the HTR2C gene may be at increased risk of weight gain and diabetes.
Polymorphisms in the HTR2A gene increase the risk of extrapyramidal symptoms (parkinsonian symptoms and dyskinesia) caused by antipsychotics.
Proactively assessing the risk of such side effects allows for a more individualized treatment plan.
Polymorphisms in the catechol-O-methyltransferase (COMT) gene, which is involved in the breakdown of dopamine, affect cognitive function and the efficacy of antipsychotic drugs.
Patients with COMT Val/Val type tend to experience faster dopamine breakdown and are more susceptible to cognitive decline.
Patients with Met/Met syndrome have high dopamine levels and are more likely to respond to the therapeutic effects of antipsychotic drugs.
4. ABCB1 gene and blood levels of antipsychotics
The ABCB1 gene encodes P-glycoprotein (P-gp) and is involved in the transport of drugs into the brain. It has been reported that polymorphisms in this gene affect the blood concentration of antipsychotics.
In patients with certain polymorphisms , the drug may not penetrate into the brain as easily, potentially resulting in insufficient efficacy.
Conversely, patients with genotypes that result in low P-gp function experience excessive drug accumulation, increasing the risk of side effects.
Summary
By utilizing genetic testing, it is possible to understand individual differences in drug effects and side effects in advance, enabling more appropriate prescriptions. Genetic polymorphisms of CYP450 enzymes and drug transporters affect the metabolic rate and blood concentration of drugs, and determine the risk of side effects. Genetic testing is being used for many drugs, including anticancer drugs, antipsychotics, antibiotics, and painkillers, and personalized medicine is progressing. It is expected that further technological innovations will enable more precise treatment in the future.
