CYP450 Genotypes and Drug Metabolism - Test # 10

Primary metabolism of many drugs is performed by cytochrome P450 (CYP), a group of oxidative/dealkylating enzymes localized in the microsomes of many tissues including the intestines and liver. The metabolism of many medications is highly variable, and can be influenced by a variety of factors. The overall or effective metabolic rate of medications depends not only on CYP genetic variations, but also on other factors such as age, sex, smoking, diet/fasting. Some of these factors can up/down-regulate the expression (i.e. quantity) and/or catalytic rate (i.e. activity) of the various enzymes of the CYP system.

At FirmaLab we use personalized genetic medicine based on patients DNA the right dosis/treatment can be designed according to patient metabolic needs.

For guidance on dosing adjustments, please see CYP Dosing Recommendations.

Normal Sample Report

Abnormal Sample Report

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CYP2D6 is the most common enzyme pathway, which only represents 1–5 % of the CYP liver content, but is wholly or partially responsible for the hydroxylation or dealkylation of up to 25% commonly prescribed drugs such as analgesics, anticonvulsants, antidepressants (SSRIs and TCAs), antipsychotics, opioids, antiarrythmics and tamoxifen, many of which have a narrow therapeutic window. Other classes of drugs metabolized wholly/partially by CYP2D6 include antiemetics, antihypertensives, antiestrogens, antineoplastics, antipsychotics, antiretrovirals, antitussives, beta-blockers, cardioactive drugs, H-2 blockers, stimulants, and sympathomimetics.

This test is focused on the prediction of or confirmation of cause ineffective medication for patients with chronic pain using narcotic analgesic medications. The test will be identified extensive (EM, normal), ultrarapid (UM), Intermediate Metabolizers (IMs), and poor metabolizers (PM). Roughly 10% of the population are PMs, they have no 2D6 enzymatic activity. Another 35% of the population are considered IMs with decreased activity. Still another 1-3% of people are UM.

The ultrarapid metabolizer (UM) phenotype is recognized as a cause of therapeutic inefficacy of antidepressant. Duplication of the functional CYP2D6 gene has been observed, which may result in ultrarapid metabolism of SSRIs and other drugs. Up to 13 copies of CYP2D6 have been reported. For these patients a pro-drug will be converted rapidly resulting in a quick spike in the serum levels but may also have a reduced duration. UMs cases of life-threatening toxicity have been reported with the prodrugs tramadol and codeine. For drugs that are metabolzied to inactive forms, UMs may require more frequent doses or alternative forms of pain relief. The poor metabolizers (PM) exhibit decreased metabolic activity, which puts them at risk for side effects to drugs normally inactivated by 2D6 (e.g., venlafaxine, metoprolol), or lack of efficacy for drugs requiring activation by 2D6 (e.g.,prodrugs such as opioids, tamoxifen). The poor metabolizers (PMs) are at risk of active drug build-up, and toxicity has been reported with several psychotropics (desipramine, venlafaxine, amitriptyline, haloperidol) and may be at risk of toxicity of metoprolol, timolol, carvedilol and propafenone. In PMs for CYP2D6, reduced analgesic effects have been observed for prodrug opioids (codeine, tramadol and oxycodone). The following table displays the CYP2D6 alleles that FirmaLab tests for.

CYP2C9 is a liver enzyme that metabolizes approximately 10% of all drugs, including warfarin, phenytoin, non-steroidal anti-inflammatory drugs (NSAIDs), and antihyperglycemic sulphonylureas.

Detecting variants of the CYP2C9 gene that cause altered enzymatic activity can identify patients who may be at increased risk of having adverse drug reactions while taking standard dosages of CYP2C9 substrates. Roughly 3% of the population are 2C9 Poor Metabolizers (PMs), meaning they have no 2C9 enzymatic activity. Another 36% of the population are considered Intermediate Metabolizers (IMs) with decreased activity. Both IMs and PMs exhibit decreased metabolic activity, which puts them at risk for side effects to drugs normally inactivated by 2C9.

With respect to warfarin, 2C9 deficiency can lead to increased bleeding risk, decreased dose requirement, and a longer time to reach stable therapy. The combination of CYP2C9 genotyping with VKORC1 - the target of warfarin’s effect – and with patient physical characteristics can accurately estimate a patient’s warfarin sensitivity level, dose requirement, and ultimately provide practitioners with better guidance for optimal INR interpretation and management. The following table displays the CYP2C9 alleles that FirmaLab tests for.

The CYP2C19 is responsible for metabolizing commonly used drugs that include clopidogrel, proton pump inhibitors (PPIs) and some antidepressants. The enzyme is highly polymorphic. The majority of the CYP2C19 PMs are carriers of the variant alleles *2 and *3.

The allelic frequency of CYP2C19*2 has been shown to be 15 % in Africans, 29–35 % in Asians, 12–15 % in Caucasians and 61 % in Oceanians. The CYP2C19*3 is mainly found in Asians (5–9 % in Asians, less than 0.5 % in Caucasians). The allelic frequency of CYP2C19*17 has been shown to be 16 % in Africans, 3–6 % in Asians and 16–21 % in Caucasians. The following table displays the CYP2C19 alleles that FirmaLab tests for.

The CYP3A4 is responsible for metabolizing about half of drugs in use today, such as acetaminophen, codeine, ciclosporin (cyclosporin), diazepam, and erythromycin. The enzyme also metabolizes some steroids and carcinogens. The majority of the CYP3A4 polymorphisms result in decreased function of the enzyme activity. The following table displays the CYP3A4 alleles that FirmaLab tests for.

The analysis of common variants in the CYP3A4, CYP2C9, CYP2C19, and CYP2D6 genes is detected by automated DNA sequencing. The genes are analyzed by PCR-based double-stranded automated sequencing in the sense and antisense directions. CYP2D6 duplication is checked by PCR based analysis followed by gel electrophoresis.

This test does not detect disease-causing mutations but rather indicates the expected metabolism of pharmaceutics and other compounds.

• Requisition form.
• Specimen and Volume: Buccal epithelial cells collected on standard cotton tip swabs. Alternative acceptable specimens include 3-5 cc of blood in EDTA or ACD BD Vacutainer tubes guide. Other types of tissue may be accepted (please call 818-789-1033 to verify before sending).
• Contact your doctor's office or FirmaLab for buccal swab kits. Buccal Swab Kit Instructions
• Temperature: can be at room temperature the specimen needs to be at the laboratory no more then 72hrs. Do not freeze whole blood.
• Turn around time: 5-7 days
• Contact FirmaLab and the laboratory will gladly provide buccal swab kits for you.

Specimen Rejection Criteria: Below are general rejection criteria. If the specimen must be rejected based on the following criteria, or specific criteria for the requested test:

1. The test requisition form has missing information. Requisition must contain the required information including:
   • Requesting party and referring authority, usually a healthcare professional.
   • Patient identifying information - Name or alias if anonymous;
   • Test requested, Clinical indication for testing;
   • Date and time of specimen collection;
   • Type of sample (e.g. whole blood or epithelial cells obtained by buccal swab);
   • All other identifying information (e.g. social security number, telephone number, hospital ID, sex … etc.) is optional, but useful for accurate differentiating between patients with similar names.
2. Label is unclear;
3. Blood specimen is from a recipient of bone marrow transplant;
4. Specimen is inappropriate for test requested;
5. Blood sample is clotted or hemolyzed;
6. Incorrect container or Vacutainer used;