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Test ID: 3A5B CYP3A5 Genotype, Blood

Useful For

Aids in optimizing treatment with tacrolimus and potentially other drugs metabolized by CYP3A5

Reporting Name

CYP3A5 Genotype, B

Specimen Type

Whole Blood EDTA


Specimen Required


Multiple whole blood EDTA genotype tests can be performed on a single specimen after a single extraction. See Multiple Whole Blood EDTA Genotype Tests in Special Instructions for a list of tests that can be ordered together.

 

Container/Tube: Lavender top (EDTA)

Specimen Volume: 3 mL

Collection Instructions: Send specimen in original tube.


Specimen Minimum Volume

1 mL

Specimen Stability Information

Specimen Type Temperature Time
Whole Blood EDTA Ambient (preferred)
  Refrigerated 

Clinical Information

CYP3A5 is 1 of the 4 CYP3 genes localized in tandem on chromosome 7 that encode the CYP3A subfamily of enzymes responsible for the metabolism of more than 50% of medications. CYP3A5 is expressed in liver, as well as extrahepatic tissue such as small intestine, lung, kidney, breast, and prostate. The CYP3A5 expression level and enzymatic activity can be modulated by genetic variation. CYP3A5 allelic frequency depends upon ethnicity. For example, in individuals of European descent the most common allele is the CYP3A5*3 allele (c.219-237A->G), which results in a splicing defect and absence of enzyme activity. In individuals of African descent, the *1 allele (functional enzyme) is most common. The distribution of CYP3A5*3 allele frequencies ranges from 0.14 among sub-Saharan Africans to 0.95 in European populations.

 

In general, most drugs metabolized by CYP3A5 are also metabolized by CYP3A4, with few exceptions. For this reason, substrates of these 2 enzymes are listed together in most publications and genotyping of both genes might be needed to fully understand the metabolism of these drugs and predict phenotype. The clinical relevance of CYP3A4 and CYP3A5 activity on drug metabolism has not been fully explored in many cases.

 

Tacrolimus is an immunosuppressive calcineurin inhibitor used in transplant recipients. Tacrolimus has a low therapeutic index with a wide range of side effects and large interindividual variability in its pharmacokinetics, particularly in the dose required to reach target trough blood concentrations, thus necessitating routine therapeutic drug monitoring in clinical practice.

 

Tacrolimus dose requirements are closely associated with CYP3A5 genotype. According to existing literature and Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, individuals with at least 1 copy of fully functional CYP3A5 (ie, *1/*1 and *1/*3) typically require a higher dose of tacrolimus to reach the targeted whole blood concentrations than those without a copy of a fully functional CYP3A5 allele (ie, *3/*3). CYP3A5*3 genotyping may predict dose requirements for tacrolimus but does not replace the need for therapeutic monitoring to guide tacrolimus dose adjustments. For a patient with the CYP3A5*3/*3 genotype, initiating tacrolimus therapy with a standard (normal) dose is recommended.

Reference Values

An interpretive report will be provided.

Interpretation

Absence of the *3 allele does not rule out the possibility that a patient harbors another variant that can impact the function of this enzyme, drug response, or drug side effects. CYP3A5 genotype is only one factor that should be taken into consideration for drug dosing.

 

CYP3A5*1/*1

Extensive (normal) metabolizer:

The CYP3A5*3 allele was not detected. Therefore, this patient is expected to be an extensive (normal) metabolizer. This phenotype is also known as CYP3A5 expresser.

 

Rapid metabolism of drugs that are inactivated or activated by CYP3A5 is expected. Patients with this phenotype should not be coadministered CYP3A5 inhibitors due to an increased risk of toxicity or lack of efficacy, respectively. For patients taking tacrolimus with this genotype, the literature indicates that higher doses may be required, presumably because original dosing guidelines were determined on patients who were poor metabolizers. Therapeutic drug monitoring is recommended.

 

CYP3A5*1/*3

Intermediate metabolizer:

One copy of the CYP3A5*3 allele was detected. Therefore, this patient is expected to be an intermediate metabolizer. This phenotype is also known as CYP3A5 expresser.

 

Reduced metabolism of drugs that are inactivated or activated by CYP3A5 is expected when compared to patients who are *1/*1. Patients with this phenotype should not be coadministered CYP3A5 inhibitors due to an increased risk of toxicity or lack of efficacy, respectively. For patients taking tacrolimus with this genotype, the literature indicates that higher doses may be required, presumably because original dosing guidelines were determined on patients who were poor metabolizers. Therapeutic drug monitoring is recommended.

 

CYP3A5*3/*3

Poor metabolizer:

Two copies of the CYP3A5*3 allele were detected. Therefore, this patient is expected to be a poor metabolizer. This phenotype is also known as CYP3A5 nonexpresser.

 

Drugs that are inactivated or activated by CYP3A5 are metabolized at greatly reduced rate when compared to patients who are *1/*1. Patients with this phenotype should not be coadministered CYP3A5 inhibitors due to an increased risk of toxicity or lack of efficacy, respectively. For patients taking tacrolimus with this genotype, the literature supports normal dosing, presumably because original dosing guidelines were determined on patients who were poor metabolizers like this patient. Therapeutic drug monitoring is recommended.

 

For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomic Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.

Clinical Reference

1. Birdwell K, Decker B, Barbrino J, et al: Clinical pharmacogenetics implementation consortium (CPIC) guidelines for CYP3A5 genotype and tacrolimus dosing. Clin Pharmaco Ther 2015:98(1):19-24 doi: 10.1002/cpt.113

2. Thervet E, Loriot MA, Barbier S, et al: Optimization of initial tacrolimus dose using pharmacogenetic testing. Clin PharmacolTher 2010;87:721-726

3. Lamba J, Hebert J, Schuetz E, et al: PharmGKB summary: very important pharmacogene information for CYP3A5. Pharmacogenet Genomics 2012 Jul; 22(7):555-558

Day(s) and Time(s) Performed

Tuesday; 8 a.m.

Analytic Time

1 day (Not reported Saturday or Sunday)

CPT Code Information

81401-CYP3A5 (cytochrome P450, family 3, subfamily A, polypeptide 5) (eg, drug metabolism), common variants (eg, *2, *3, *4, *5, *6)

LOINC Code Information

Test ID Test Order Name Order LOINC Value
3A5B CYP3A5 Genotype, B 81140-6

 

Result ID Test Result Name Result LOINC Value
36675 CYP3A5 Phenotype 79717-5
36674 CYP3A5 Star Alelles In Process
36676 3A5 Interpretation 69047-9
36677 Reviewed by No LOINC Needed

Method Name

Polymerase Chain Reaction (PCR) 5'-Nuclease End-Point Allelic Discrimination Analysis

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.

Forms

1. New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (T576) is available in Special Instructions.

2. If not ordering electronically, complete, print, and send a Neurology Specialty Testing Client Test Request (T732) with the specimen (http://www.mayomedicallaboratories.com/it-mmfiles/neurology-request-form.pdf)

Mayo Medical Laboratories | Genetics and Pharmacogenomics Catalog Additional Information:

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