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Pharmacogenetics
Impact of Pharmacogenetic Testing
Although it has long been recognized that many human diseases are caused by genetic mutations, it is less widely appreciated that known genetic variants influence how we respond to certain drugs. This class of genetic testing is called pharmacogenetics.1,2 According to the US Food and Drug Administration, a medication is classified as having a narrow therapeutic index (NTI) if small changes in the dosage level produce toxic or subtherapeutic effects.3,4 The goal of pharmacogenetic testing is to identify patients who will benefit from modified dosage regimens necessary to enhance therapeutic benefit, while at the same time reducing the incidence of adverse reactions. This personalized approach to treatment enables rational optimization of drug dosage early in the treatment cycle, thus improving on the inefficient “trial-and-error” methodology used traditionally. This approach to patient care is rapidly gaining acceptance and has a major role to play in the chemotherapeutic treatment of cancer.
LabCorp, a leader in pharmacogenetic testing, offers the following tests
Cytochrome P450
Managing medication dosing and reducing adverse drug reactions
Cytochrome P450 (CYP) is a major group of drug-metabolizing enzymes (DME) that consists of more than 50 isoforms. The majority of CYP activity takes place in the liver. Variants in the P450 enzymes can result in altered drug metabolism that could lead to adverse drug reactions.
Table 1.—Phenotypes Associated With CYP450 Variants5,6
Phenotype |
Definition |
Active Drug Concerns
|
Prodrug Concerns
|
| Poor metabolizer(PM) |
Significantly reduced or absent enzyme activity5,6 |
Drug metabolized slowly or not at all, increased concentrations of active drug, potential for serious side effects due to increased concentration of active drug5 |
May not respond due to lack of (or reduced amounts of) active metabolite5 |
| Intermediate metabolizer (IM) |
Reduced enzyme
Activity5,6 |
May experience some, if any, consequences of
poor metabolizers5
|
May experience some (if any) consequences of poor metabolizers5
|
| Ultrarapid metabolizer (UM) |
More than two copies of active enzymes5,6 |
May not reach therapeutic levels of active drug due to rapid clearance5 |
May reach higher than expected concentrations of active metabolite, which may cause adverse reactions5
|
| Normal extensive metabolizer (EM) |
Activity is "normal"- wildtype5,6 |
Expected response to standard dose5 |
Expected response to standard dose5 |
2D6
CYP2D6 is one of the most important DME genes as it metabolizes 25% to 30% of all prescribed drugs.5,7 Common drug categories metabolized by CYP2D6 include (but are not limited to): beta blockers, antiarrhythmics, morphine derivatives, and antidepressants.5
Ordering Information for Cytochrome P450 2D6 Genotyping (511160)
For more information 
2C19
CYP2C19 metabolizes 15% of all prescribed drugs.5 It is important in the metabolism of antiarrhythmics, proton pump inhibitors, and antidepressants.5 The package insert of many medications includes information on how that particular drug is metabolized and may indicate when CYP2D6 and/or CYP2C19 genotyping is beneficial.8
Ordering Information for Cytochrome P450 2C19 Genotyping (511320)
For more information
2D6/2C19
Together, CYP2D6 and CYP2C19 are involved most commonly in psychotropic drug metabolism.8,9
Ordering Information for the Cytochrome AmpliChip™ P450 2D6/2C19 Genotyping and Phenotyping (511316)
To learn more about Cytochrome P450 2D6 and 2C19 testing,
view the LabCorp LabCapsule or visit www.amplichip.us.
2C9
Several common drug categories metabolized by 2C9 include, but are not limited to, anticoagulants [S-warfarin], antiepileptics [phenytoin], nonsteroidal antiinflammatory drugs [aspirin, diclofenac, naproxen], antidiabetic drugs [glipizide, glyburide, tolbutamide], and antihypertensives [losartan].10,11
Ordering information for Cytochrome P450 2C9 Genotyping (511270)
For additional information, view the LabCorp LabCapsule.
UGT1A1 Irinotecan Toxicity
Managing medication dosing and predicting response to treatment of cancer with irinotecan (Camptosar®, CPT-11)
LabCorp offers pharmacogenetic testing for UGT1A1, an enzyme that metabolizes irinotecan, which is commonly prescribed for patients with colorectal cancer. Toxicity due to irinotecan is commonly observed in cancer patients who carry the UGT1A1*28 allele.12,13 These patients may benefit from a lower starting dose of irinotecan. The adverse reactions that any given patient may encounter underscores the need to evaluate the UGT1A1 genotype as an essential component of any treatment regimen with irinotecan.
Pharmacogenetic testing is used to identify patients who will benefit from modified dosage regimens necessary to enhance therapeutic benefit, while at the same time reducing the incidence of adverse reactions.
Ordering information for UGT1A1 Irinotecan Toxicity (511200)
For additional information, view the LabCorp LabCapsule
DPD 5-Fluorouracil Toxicity
Managing medication dosing and predicting response to treatment of cancer with 5-fluorouracil
The chemotherapy drug 5-fluorouracil (5-FU) is a common treatment for cancer because of its broad-spectrum application, which includes colorectal, gastric, pancreatic, head, neck, breast, ovarian, and cervical cancers.14 Some patients, however, are genetically predisposed to adverse reactions to this drug. Unfortunately, no outward clinical manifestations define which patients are susceptible to 5-FU toxicity.
LabCorp offers pharmacogenetic testing for dihydropyrimidine dehydrogenase (DPYD), a gene that plays a key role in the metabolism of 5-FU. A DPD deficiency is recognized as a risk factor that predisposes patients to 5-FU toxicity. LabCorp’s assay tests for the most common DPYD gene mutation, IVS14+1 G>A, also known as *2A. Detecting the DPYD IVS14+1 G>A mutation provides critical information for making appropriate therapeutic decisions.
Pharmacogenetic testing is used to identify patients who will benefit from modified dosage regimens necessary to enhance therapeutic benefit, while at the same time reducing the incidence of adverse reactions.
Ordering information for DPD-5 Fluorouracil Toxicity (511176)
For additional information, view the LabCorp LabCapsule
References
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