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Drug Metabolism

Drug Sensitivity and Your Genetics

By | Adverse Drug Reactions, Drug Metabolism | No Comments

Drug sensitivity is broadly defined as an exaggerated response to a drug in a patient in comparison to the expected response in the general population. Drug sensitivity can range from increased side effects to complete drug intolerance, whereby patients exhibit severe side effects or death. These side effects are often irreversible, as in aspirin induced Tinnitus.


Why Do Some People Suffer from Drug Sensitivity?

Drug sensitivity should not be confused with drug hypersensitivity. Drug hypersensitivities are caused by a patient’s body mounting an immune response to a drug. These can also be severe, but are different to drug sensitivities. Drug sensitivity results solely from genetic differences in a patient. How can your genetics impact drug metabolism and action? Through polymorphisms of genes coding for enzymes or receptors that directly affect how the body responds to the drug.
For instance, an article in Pharmacogenetics and Genomics “VKORC1 Pharmacogenomics Summary” (Oct 2011) states that polymorphisms in the gene VKORC1, which codes for the enzyme Vitamin K epoxide reductase, regulates a patient’s sensitivity to the common anti-coagulant drug Warfarin. The enzyme is the limiting step in the vitamin K cycle and Warfarin acts to inhibit this enzyme, inhibiting Vitamin K’s downstream coagulation effects. Variants 1639A and 1173T require a lower Warfarin dose whereas patients with allele 9041A need a higher dose.

Drug Intolerance and Severe Side Effects 

Drug intolerance can cause severe side effects in a patient. These are usually rare but in some instances are reasonably common. For instance, Tinnitus is a drug intolerant side effect to the drug Aspirin. At higher doses, aspirin is nown to cause tinnitus according to a study Frontiers in Systems Neuroscience “Salicylate toxicity model of tinnitus” (April 2012), but some patients experience the symptom after a normal dose of the drug.
Other examples of drug intolerance include liver failure to Paracetamol, fatal poisoning in infants who breastfeed on mothers who are taking the pain relief drug codeine, hypotension (low blood pressure) in patients taking heart drug Enalapril and hallucinations in patients taking codeine, according to research in Australian Family Physician, “Adverse drug reactions” (Feb 2013).
The number of genes that might cause drug sensitivity is massive and many are still not known. At Rxight® we sequence VKORC1 and a panel of other genes to identify how patients will react to more than 200 clinically relevant medications. Genetic testing for drug sensitivity is a faster, cheaper and far safer alternative than watching patients undergo adverse drug reactions and adjusting the dose accordingly.

Drug Metabolism Testing with Rxight®

By | Drug Metabolism | No Comments


Both clinicians and patients know that drugs can cause side effects. However, not all patients experience side effects. Variability in drug response is due to many factors including age, weight, number of medications taken and overall health. Genetic variation is also a reason that a patient may experience an adverse reaction to a drug. Pharmacogenetics studies the way that variations in a patient’s genetic makeup affect the metabolism of drugs. Rxight® genetic testing examines specific genes associated with drug metabolism to determine whether an individual’s inherited characteristics may cause side effects, toxicity or result in no therapeutic value.


Drug Metabolism and Adverse Reactions


To avoid adverse reactions, doctors often use a trial and error method to find appropriate medications for patients. Pharmacogenetic testing provides important information about which medicines may cause unpleasant side effects. Testing also helps clinicians find doses of medications that are appropriate for a patient’s genetic characteristics.


Genetic variants affect the rate of assimilation of a drug by the body. Poor metabolism of a drug can cause adverse effects because the drug stays in the body too long. Ultra-rapid metabolism may result in no benefit from the drug because it is eliminated too quickly.


The cytochrome P450 enzymes are responsible for approximately 70 percent of drug metabolism. Of the approximately 60 cytochrome P450 genes, six are known to affect drug metabolism and drug-drug interactions. The most significant are CYP2C19, CYP2C9 and CYP2D6.


CYP2D6 is responsible for the metabolism of approximately 25 percent of prescription medications. Drugs metabolized by this gene include many antidepressants, beta-blockers, opioids and anti-cancer medicines. Codeine, a pro-drug, is inactive until it is converted by gene CYP2D6 to morphine. Poor metabolizers of codeine do not get any pain relief. Ultra-rapid metabolizers of codeine convert the drug into morphine too rapidly, which may result in side effects or toxicity. The Food and Drug Administration recommends that codeine not be prescribed to nursing mothers who are ultra-rapid metabolizers of CYP2D6 because large amounts of morphine passed through breastmilk can result in infant respiratory failure or death.


Approximately 30 variants have been identified for gene CYP2C19. This gene is responsible for the metabolism of clopidogrel, a commonly prescribed antiplatelet medication used by patients with heart disease. Extensive and poor metabolizers have a higher incidence of adverse reactions to this drug. The FDA recommends use of another medication for patients with genetic variants that affect the metabolism of this drug.


Rxight® Pharmacogenetic Testing

Rxight® pharmacogenetic testing examines 18 genes that have known associations with drug metabolism, including the six major cytochrome P450 enzymes. A sample of a patient’s DNA is taken by a certified pharmacist and sent to MD Labs for analysis. A detailed report, included in the cost, is provided to each patient and interpreted by the pharmacist. Rxight® certified pharmacists consult with clinicians to ensure that the prescribed medication therapy regimen is best suited for the patient’s genetic characteristics. Doctors can select medicines and doses that may result in fewer side effects and provide better therapeutic value. Patients are more likely to take their medicine when they know that the potential for side effects is reduced. Better adherence to a drug therapy program helps maintain health.

statins side effects

Statin Side Effects in Women

By | Drug Metabolism, Pharmacogenetic Testing, Pharmacogenomics, Precision Medicine, Statins | No Comments

Statin treatment in women without cardiovascular disease is controversial. Research has found that for women with elevated LDL levels as their only cardiovascular risk factor, the benefit of lowering LDL cholesterol with a statin drug might not outweigh the risks.
According to an article in Circulation “Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia” (March 2010) many women take statins and suffer side effects similar to those experienced by men. Statin side effects range from mild to severe and include liver damage, myopathy, and behavioral and cognitive problems.

Revised Treatment Guidelines Push for Increasing Statin Use

Treatment guidelines issued in 2014 in the New England Journal of Medicine suggest that up to 13 million more adults should be taking statins. The revised guidelines changed the focus from specific cholesterol levels to a wider assessment of heart attack and stroke risk.

Opponents Claim Too Many Women Prescribed Statins

Not everyone agrees with these new treatment guidelines, as reported in the New York Times, also in 2014: “Among men 60 to 75, the percentage would jump to 87 percent from 30 percent; among older women, it would increase to 54 percent from 21 percent.” In that New York Times article, the chief of cardiovascular medicine at the Cleveland Clinic said the report confirmed his concerns that the new guidelines “don’t target the right patients for treatment.” He faulted the study for not taking into account the family history of cardiovascular disease: “Should so many women be taking statins? Far too many healthy women are taking statins, they say, though some research indicates the drugs will do them little good and may be more likely to cause serious side effects in women.”

Women Found to Suffer More Side Effects from Statins Than Men

These studies highlight the fact that fewer women take statins than men, and that women suffer more side effects from statins than men. Although women represent about half the population, they are enormously under-represented in clinical trials of statins. It follows that the evidence on the benefits and risks for women is scarce. In one of the studies American Journal of Cardiology “Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)” (Jan 2006), there was no significant reduction in heart attacks, strokes and deaths among the women while the male participants on statins had fewer heart attacks and strokes.

Weigh the Risks and Benefits with Genetic Testing

Some side effects of statins and other drugs may be reduced by either altering the dose or by changing the particular statin prescribed. Side effects in general may be reduced by taking into account the variation in your drug metabolism genes. The study of variation in the drug metabolism genes defines the field of Pharmacogenetics. This advanced genomics field emerged after the human genome was sequenced and has become an important field of its own.

Rxight® Pharmacogenetic Testing for Statin Side Effects

Pharmacogenetics research showed there is variation in the genes that are responsible for processing drugs. That means that if a particular gene has variations it may result in a gene product (protein or enzyme) that is non-functional or has reduced function. This altered function, which can sometimes mean an inability to process a medication or a reduced ability to process a medication, may result in adverse side effects. Side effects may be lessened by avoiding those drugs that you don’t have the ability to process normally.

Once you and your physSician have these results you can use them for your lifetime. The results allow your physician to interpret your ability to metabolize over 200 drugs on the market. Your physician will then have at hand the predictive ability to prescribe drugs that are safer for you and to possibly avoid side effects with any new medication. With the Rxight® pharmacogenetic test from MD Labs you can bring precision medicine home to your personalized medical care.

About Statin Myopathy

By | Adverse Drug Reactions, Drug Metabolism, Statins | No Comments


What are Statins?

Statins are the primary class of lipid lowering medications used to lower serum cholesterol for both primary and secondary prevention of coronary disease.  They inhibit the enzyme HMG-CoA reductase which plays a central role in the production of cholesterol. Statin therapy is successful in reducing cholesterol and thus, limiting the incidence of cardiovascular events.


Myalgia, Myositis, Rhabdomyolysis

Statin myopathy is separated into three different types based on toxicity such as myalgia, myositis and rhabdomyolysis.  Myalgia refers to generalized pain in the muscles, while myositis presents itself with muscle pain, tenderness, weakness and a higher blood level of creatine kinase.  Rhabdomyolysis is an extreme, life threatening type of myopathy.  Myalgia can occur with or without serum creatine kinase elevation, a marker for muscle damage.  Myositis has a higher level of creatine kinase in the bloodstream.  The most extreme, life-threatening type of myopathy, rhabdomyolysis, can display up to 10 times greater creatine kinase levels.  This can be fatal due to acute renal failure.


What Causes Statin Myopathy?

The way in which statin myopathy occurs is not well understood.  Statins are HMG-CoA reductase inhibitors and prevent the conversion of HMG-CoA to mevalonic acid, an early step in cholesterol biosynthesis.  Individual statins may have specific effects on the synthesis of coenzyme Q10, which plays an important role in muscle cell energy production.  Conflicting studies have come to different conclusions about whether statins decrease the levels of ubiquinone in skeletal muscle. The jury is still out on what exactly causes statin myopathy adverse effects, but many studies are focusing on additional genes and proteins involved in lipid metabolism. Most statins undergo CYP3A4-mediated biotransformation, and variations in this gene may be responsible for statin muscle myopathy.


Statin Myopathy and Pharmacogenetic Testing

Once the human genome was sequenced, pharmacogenomics emerged in the form of genome wide association studies, which showed that many people have gene variations that are responsible for medication adverse reactions.  Testing is available from MD Labs with the Rxight®  pharmacogenetic testing.  All that is required is a prescription from your physician to see your pharmacist for a cheek swab.  The results may be used by you and the prescriber over the lifetime of your individual care, as the test determines your genetic variations with respect to drug metabolism for over 200 drugs.








tegretol side effects

Study Details Genetic Influence on Carbamazepine Adverse Reactions

By | Adverse Drug Reactions, Drug Metabolism, Provider | No Comments

Carbamazepine (branded as Tegretol) is an anticonvulsant that is used to treat seizures and bipolar disorder among other psychiatric conditions. As effective as the drug is at treating such diseases, patients can suffer from potentially fatal or disfiguring adverse reactions.
The primary genetic culprit behind such severe reactions is HLA-B*15:02, according to a recent University of Liverpool study. The findings were published in Pharmacogenomics and Personalized Medicine “The HLA-A*31:01 allele: influence on carbamazepine treatment,” (November 2016).

“There is no doubt that there is an association between HLA-A*31:01 and CBZ hypersensitivity, in particular to HSS, in many different ethnic groups,” the authors state, noting that ethnic groups such as Asian population are at greater risk.

What is the HLA-B*15:02 Allele?


HLA-B*15:02 is an human leukocyte antigen (HLA) allele which is involved in the body’s inflammation response, as encoded by white cells (leukocytes). Specifically, the HLA s is a gene complex encoding the major histocompatibility complex (MHC) proteins in humans. The proteins encoded by certain genes are also known as antigens.


Adverse Reactions in Genetically Susceptible Patients


Severe adverse reactions can occur in genetically susceptible patients who are administered carbamazepine. Side effects include: toxic epidermal necrolysis (TEN), Stevens–Johnson syndrome (SJS), hypersensitivity syndrome (HSS) and milder reactions, such as maculopapular exanthema (MPE). Such reactions can be severe, life-threatening and disfiguring, the study noted.

“The mortality rate of TEN at 1 year is 34%, and in pediatric patients who survived acute TEN, all patients suffered with long-term complications, which included scarring, visual loss and chronic kidney disease,” according to the article.

Researchers Call for Pharmacogenetic Screening

The study identifies the challenges in applying pharmacogenetic screening for HLA-A*31:01 and proposals for overcoming these barriers. Specifically, the study notes that currently the carbamazepine summary of product characteristics approved by the European Medicines Agency for testing for HLA alleles mandates testing for HLA-B*15:02 before the use of CBZ in certain ethnic groups, but mentions HLA-A*31:01 for information only.
“At present, there is a disconnect between health technology assessment and regulatory advice, the authors state. “For precision medicine to succeed, we need to look at all forms of evidence, rather than relying on the usual paradigm of prospective studies or randomized trials.”

Understand Your Risks with the Rxight® Genetic Test

MD Labs’ Rxight® pharmacogenetic testing is based on the analysis of a comprehensive genetic panel identify whether genetic variants are present that put patients at risk for side effects or medication inefficacy. Over 200 medications across over 50 clinically significant pharmacological classes are tested ( including carbamazepine). All that is required is a simple cheek swab which is sent to our lab for analysis. The results, which are reviewed in detail with patients, are designed to guide prescribers in devising treatment plans that are based in the patient’s unique genotype.








Adderall Side Effects

By | ADHD Medications, Adverse Drug Reactions, Drug Metabolism | No Comments



Amphetamine, commonly known by its trade names Adderall, Dyanavel XR and Evekeo, is a stimulant drug used in the treatment of a number of disorders including ADHD (attention deficit hyperactivity disorder), narcolepsy, depression, and obesity.


Adderall Mechanism of Action


Adderall is a strong neurostimulator. It causes the release of noradrenaline (norepinephrine) from adrenergic presynaptic neurons. Norepinephrine is a central nervous system stimulant, and this stimulant effect is thought to underlie the drugs therapeutic actions in ADHD.


Common Side Effect of Amphetamines


Adderall is usually a well tolerated drug with few side effects. However it is associated with a number of ADHD medication adverse reactions. These include (occur in more than 1% of patients):


  • Epistaxis (nose bleeds)
  • Allergic rhinitis (stuffy nose)
  • Upper abdominal pain


Less Common Side Effects of Amphetamines

A number of side effects have been reported when taking amphetamine (Adderall) but have not had their frequency reported in large scale trials. These side effects include:


  • Euphoria
  • Dysphoria
  • Insomnia
  • Restlessness
  • Dizziness
  • Dyskinesia (involuntary movement)
  • Tremor
  • Headaches
  • Dry mouth
  • Diarrhea
  • Constipation
  • Impotence
  • Frequent erections
  • Increase libido
  • Decreased libido
  • Weight loss
  • Anorexia


How Does Pharmacogenetic Testing Work?


As previously mentioned, Adderall is usually a well-tolerated drug that has few side effects in most patients. However, a small portion of individuals will suffer multiple severe adverse reactions. This inter-patient variation is partially accounted for by the genetic differences between individuals. Polymorphisms in genes that code for receptors and enzymes that interact with amphetamine could increase the probability of developing side effects when taking the drug.


For instance, amphetamine is metabolized by the cytochrome P450 superfamily of enzymes, namely isoenzyme CYP2D6. Studies have suggested that polymorphisms in CYP2D could increase the probability of developing side effects when taking Amphetamine. Other studies have suggested that variants in the mu opioid receptor OPRM1 mediated the euphoria often seen in patients taking Amphetamine.


Understand Your Risks with the Rxight® Genetic Test


Identifying these polymorphisms can therefore aid a clinician’s decision making when prescribing amphetamine and other ADHD stimulant medications. A clinician may lower the dose given a specific allele or recommend the drug not be prescribed at all. Unfortunately routine genomic screening in not performed by most health care providers. MD Labs’ genetic testing program, Rxight®, sequences 18 genes (including OPRM1 and CYP2D6) to establish how a patient is likely to respond to hundreds of clinically relevant medications (including Adderall).








Psychiatric Medication Side Effects

By | ADHD Medications, Adverse Drug Reactions, Antipsychotics, Drug Metabolism, Psychiatric Medications | No Comments

Learn More about Our Genetic Test to Find Your Risks for Side Effects

Almost 79 million Americans use some form of psychotropic drug. Psychiatric medications include antidepressants, antipsychotics, anti-anxiety drugs, mood stabilizers and stimulants used to treat mental health conditions such as anxiety, depression, attention deficit disorder and schizophrenia. Some are used for non-psychological ailments including pain and neuropathy.


Common Side Effects of Psychiatric Medications

Most psychiatric drugs have side effects, although not every patient experiences adverse effects. Common side effects include blurred vision, headaches, nausea and drowsiness. A small percentage of patients experience severe or life-threatening adverse reactions such as fever, seizures or difficulty breathing. These drugs must be used under the supervision of a clinician. Patients must strictly adhere to prescription protocols to avoid side effects, drug interactions or withdrawal symptoms.


Adverse reactions to psychiatric drugs occur for a number of reasons including diet, type and severity of disease and use of other medications. Some reactions occur because of a person’s unique genetic makeup. Studies demonstrate that particular genes affect the metabolism of specific medicines. Pharmacogenetics looks at the way an individual metabolizes and responds to drugs. Knowing a patient’s genetic characteristics allows clinicians to select medications that have the greatest therapeutic value and minimize adverse drug events.


Antidepressants Side Effects


Antidepressants are used to treat several conditions including depression, anxiety, pain, smoking cessation, neuropathic pain and sleep disorders. These drugs correct chemical imbalances in the brain. Neurotransmitters, chemicals produced by nerve cells in the brain that communicate with one another, include dopamine, gamma-aminobutyric acid, norepinephrine and serotonin. Antidepressants inhibit chemical imbalances and enhance communication between cells.


Older antidepressants include monoamine oxidase inhibitors such as selegiline, tetracyclics such as mirtazapine and tricyclics such as amitriptyline. MAOIs may produce side effects such as muscle cramps, low blood pressure and weight gain. MAOIs also interact with certain foods, so dietary restrictions are necessary. Common side effects of tricyclics and tetracyclics include constipation, dizziness and dry mouth. More serious side effects include thoughts of suicide, vomiting and hives.


Newer antidepressants include serotonin reuptake inhibitors such as fluoxetine and sertraline, and serotonin and norepinephrine reuptake inhibitors such as duloxetine and bupropion. These drugs are more commonly prescribed because they produce fewer adverse reactions. Side effects of SSRIs and SNRIs include agitation, sweating and abnormal thinking. These drugs should not be combined with other medicines or herbs that increase serotonin levels in the brain such as older antidepressants, St. John’s Wort or amphetamines. Drug interactions may cause a life-threatening condition called serotonin syndrome or gastric bleeding.


Clinicians typically prescribe antidepressants by trial and error to determine whether a patient will suffer adverse reactions and find a dosage that controls symptoms while minimizing side effects. When patients suffer side effects or do not get relief, the doctor may change medicines. Antidepressants should be stopped only under the guidance of a healthcare professional to avoid relapse or serious side effects.


Anti-Anxiety Drugs Side Effects

Anti-anxiety medicines are used to treat anxiety disorders such as panic attacks, phobias and excessive worry. Most medicines in this category are benzodiazepines such as clonazepam, chlordiazepoxide and diazepam. Beta-blockers such as propranolol and antihistamines such as hydroxyzine are also used to treat anxiety. Like depression, anxiety disorders often occur because of chemical imbalances in the brain. Although these medicines cannot cure the disorders, they can provide relief from symptoms. Benzodiazepines target GABA transmitters, while antihistamines provide a sedative effect. Beta-blockers ease anxiety such as stage fright or post-traumatic stress. Anticonvulsants such as gabapentin and topiramate are often used to augment therapy.


Each of these medications may produce minor side effects such as dizziness, fatigue or drowsiness. Benzodiazepines are usually used on a short-term basis because they can be habit-forming. They should not be stopped abruptly because of the risk of side effects and seizures or be combined with alcohol or other central nervous system depressants. Beta-blockers should not be used by people with asthma or diabetes. Some anticonvulsants like topiramate are associated with visual changes and decreased sweating. Anticonvulsants should be stopped gradually to avoid the risk of seizure. Combining anti-anxiety drugs with other medications should be done only under the guidance of a physician to avoid serious side effects from drug interactions.


Side Effects of Antipsychotics


Antipsychotics are used to manage mental disorders including psychosis, schizophrenia, delirium and dementia. Antipsychotics block dopamine receptors. Older medicines, called “typical” antipsychotics or neuroleptics, include chloropromazine and haloperidol. Newer drugs, called “atypical” antipsychotics, act on both dopamine and serotonin receptors. Atypical antipsychotics include risperidone and lurasidone. Common side effects of atypical
antipsychotics include tremors, seizures, constipation and restlessness. Typical antipsychotics may also impair movement or cause rigidity or muscle spasms. Long-term use may cause tardive dyskinesia, or uncontrollable movements around the mouth. Antipsychotics should not be stopped abruptly to avoid withdrawal symptoms.


Stimulants Side Effects


Stimulants increase heart rate, attention and blood pressure. They are used to treat attention deficit hyperactivity disorder, depression and other health conditions. Medicines used to treat ADHD include dextroamphetamine and methylphenidate. Common side effects include sleeplessness and loss of appetite.


Mood Stabilizer Side Effects


Mood stabilizers are used to treat mood swings and bipolar disorder. They may also be used with other psychiatric drugs to treat other mental health problems. Lithium is commonly used for these disorders. Anticonvulsants such as carbamazepine and valproic acid are also used. Side effects include itching, blackouts, seizures or loss of coordination.


Pharmacogenetic Testing and Adverse Drug Reactions


Pharmacogenetic testing examines a patient’s DNA to identify gene variants that can affect the metabolism of drugs. The cytochrome P450 family of genes metabolizes most psychiatric drugs. Genetic variations can affect the rate of metabolism. Slow metabolism may result in adverse side effects. Rapid metabolism may eliminate a drug too quickly and reduce the therapeutic value.


Some genes affect the metabolism of antipsychotic medicines that bind with dopamine. Other genes affect how SSRIs are assimilated. Some variants are common to particular ethnic groups; others are individual. Studies show that particular genotypes had a 50 percent higher risk of developing tardive dyskinesia. Another genetic variant is associated with a reduced risk of TD, suggesting the gene may protect from developing TD. Drugs such as clozapine that bind with serotonin receptors are associated with lower incidences of TD.


Gene CYP2D6  metabolizes several antidepressants and approximately 40 percent of antipsychotics including risperidone and haloperidol. Poor metabolizers of CYP2D6 are more likely to suffer side effects from several commonly prescribed antipsychotics. Genotyping for CYP2D6 can help predict metabolic responses for several antidepressants and neuroleptics. The Food and Drug Administration has issued drug label warnings and dosing recommendations for specific genetic variants for several psychiatric drugs including clozapine, risperidone and amitriptyline.


Clinicians and pharmacists trained in pharmacogenetics can help patients understand the potential for adverse effects of psychiatric drugs that may be due to genetic variants. When testing results are included in a patient’s medical records, pharmacists can verify that medications are appropriately dosed and communicate information about how to use the drug to patients. Reducing side effects makes patients more confident about the medications prescribed by their doctors, which can increase patient adherence to drug therapy regimens.







P450 Enzymes and Drug Metabolism

By | Drug Metabolism | No Comments

Cytochrome P450s (sometimes referred to as CYPs) are proteins involved in almost 75% of phase I drug metabolism. They are part of the heme cofactor superfamily and therefore hemoproteins. The active site of the P450 enzyme contains a heme-iron center. Most P450 enzymes will require a separate protein to deliver one of more electrons to reduce the heme-iron centre. They are predominantly involved in Phase I metabolism. The P450 enzymes are present in hundreds of isoforms in the human body. Different isoforms of P450 results in different reactions catalyzed and different molecules regulating that catalysis.


P450 Test

As P450’s are so important to drug metabolism, understanding genetic abnormalities in these enzymes can be a real help when it comes to pharmacotherapy. For instance, knowing a patient has a polymorphism of CYP2D6 that results in rapid metabolism of codeine will indicate that this patient will not see much pain relief from the drug.


The Rxight® genetic test covers a number of P450 enzymes. These are:

  • CYP2B6
  • CYP2C8
  • CYP2C9
  • CYP2C19
  • CYP2D6
  • CYP3A4/CYP3A5

Within these, CYP2C9, CYP2C19 and CYP2D6 are of significant importance, accounting for almost 35% of all phase I metabolism of clinically used drugs.


The P450 enzyme CYP2C9 is of significance in the breakdown of the commonly used anticoagulant warfarin. Polymorphisms in CYP2C9 account for a significant proportion of variation in dose requirements.


CYP2C19 is required for metabolism of 10% of medicines used today. It metabolizes a number of anti-ulcer drugs including the proton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, etc.). It has other clinically important polymorphisms regarding platelet drugs such as clopidogrel. These mutations can result in excessive anticoagulation and increase the risk of bleeds, or can result in little to no response from the drug.


CYP2D6 can result in the reactions discussed above relating to the opiate codeine, but it is also responsible for metabolizing a number of tricyclic antidepressants. Some polymorphisms can result in no response from the drug, or can result in drug reactions (e.g., serotonin syndrome).







Learn about Drug Metabolism

By | Drug Metabolism | No Comments

Drug Metabolism


Drug metabolism is incredibly important for the efficacy of a drug. Decreases in hepatic activity can result in increased blood concentration of said drug. This might result in an increased risk of drug toxicity or side effects. Counter to this, increased hepatic metabolism results in decreased blood concentration of a drug and decreased therapeutic effect.


Drug metabolism is largely controlled by the liver and involves three distinct phases. Phase I reactions add a functional group (for instance -OH or NH2), increase the polarity of the drug and provide a site for phase II reactions. Phase II reactions almost always result in the drug becoming physiologically inactive. The drug will also become more hydrophilic, making excretion (phase III) easier.



Metabolizing enzymes:


Phase I reactions usually involve adding a functional group. As such reductions, hydrolysis and oxidation are all common reactions. Some 75% of these are controlled by the Cytochrome P450 (or CYP) enzyme family. CYP enzymes are part of the heme cofactor superfamily and thus described as hemoproteins. Several hundred isoforms of P450 enzymes exist. These isoforms differ in amino acid sequence, resulting in differences in the molecules that regulate them (eg inhibit or induce) and in the reactions they catalyze.


CYP metabolism and CYP2D6 metabolism


As drug metabolism is so important for the efficacy of a given drug, we screen for polymorphisms in a number of CYP metabolizing enzymes. These include:


  • CYP2B6
  • CYP2C8
  • CYP2C9
  • CYP2C19
  • CYPD6
  • CYP4A4/CYP3A5


Taking CYPD6 as an example, the enzyme is involved in the metabolism of 25% of all clinically important medications. Hepatic enzyme CYP2D6 is clinically relevant because polymorphisms can interrupt the conversion of codeine to its active form, morphine. The gene encoding CYP2D6 has a differential expression in just over 1% of the population.


In a portion of this 1% CYP2D6 is a poor metabolizer of codeine. These individuals cannot convert codeine to morphine and gain no pain relief from the drug. They also exhibit exaggerated side effects of codeine as its blood concentration is higher for longer. Another polymorphism of CYP2D6 results in ultra rapid metabolism resulting in toxic levels of morphine. This is some in Table 1.



Genetic screening with
Rxight® means that these polymorphisms are identified before the individual suffers adverse side effects. Pain treatment is faster and more specific.


This is just one example of variability associated with a CYP2D6 assay. Other drugs metabolised by the enzyme include:


  • Desipramine
  • Imipramine
  • Amitriptyline
  • Haloperidol
  • Venlafaxine
  • Risperidone


Pharmacogenetic testing thus can provide a simple and effective way to reduce side effects and provide a more targeted therapy to patients.