Cytochrome P450 3A4/3A5 Genotyping

CPT: 81401(x2)
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Test Details

Use

This test provides genotypes for CYP3A4 and CYP3A5 and determines estimated metabolic activity. CYP3A4 and CYP3A5 cytochrome P450 enzymes are involved in the hepatic metabolism of up to 50% of all clinically used drugs. There is wide variation in enzyme activity, particularly for CYP3A4 (10-100 fold), due to both genetic and nongenetic factors. The cause of much of the variation is not yet understood.

Limitations

This assay detects CYP3A4 alleles *1 and *22, and CYP3A5 alleles *1, *3, *6, *7. Other alleles are not detected by this assay. Metabolism of drugs may also be influenced by race, ethnicity, diet, and/or other medications. Results must be interpreted in the context of other test results and clinical findings. This test result does not rule out the possibility of variant alleles in other drug metabolism pathways that may affect drug efficacy and/or toxicity.

Methodology

Multiplex polymerase chain reaction (PCR) and primer extension

Additional Information

The CYP3A4 and CYP3A5 enzymes have a high degree of similarity (85% amino acid sequence homology), and they metabolize largely the same set of drugs, though many use the CYP3A4 pathway predominantly. Genotype and metabolic activity for CYP3A4 and CYP3A5 should, therefore, be considered together when assessing possible effects on drug response. CYP3A4 *22 decreases enzyme activity and is present in approximately 8% of Caucasians. CYP3A5 *3 is a nonfunctional allele, so CYPA5 *3/*3 homozygotes are nonexpressors of CYP3A5. CYP3A5 *3 is the predominant CYP3A5 allele in Caucasians (prevalence of approximately 92%) and, therefore, most Caucasians have reduced or absent CYP3A5 metabolism. CYP3A5 *6 and *7 are also nonfunctional alleles with absent enzyme activity. CYP3A5 *6 and *7 are present in 11% to12% of Asians and African Americans, but are essentially absent in Caucasians (frequency of 0.1%). CYP3A4 *22 is typically associated with increased response to statins (lovastatin, simvastatin, and atorvastatin), with lower doses required to gain optimal response.

For CYP3A5, poor metabolizers are typically expected to require standard dosing of tacrolimus. Intermediate or extensive metabolizers are expected to require a higher starting dose of tacrolimus. Fentanyl is a key pain medication that is metabolized by CYP3A4/3A5. The CYP3A5 *3 variant has decreased clearance of this active drug. Patients with the CYP3A5 *3/*3 genotype have a higher risk of adverse events than patients with one or two *1 alleles; however, the CYP3A genotype and clinical variables (delivery rate, gender, comedications, kidney disease, BMI, and serum albumin) account for less than 50% of the wide variability in serum fentanyl concentration between patients with transdermal fentanyl treatment.

Specimen Requirements

Specimen

Whole blood or LabCorp buccal swab kit (The buccal swab collection kit contains instructions for the use of a buccal swab.)

Volume

7 mL whole blood or LabCorp buccal swab kit

Minimum Volume

3 mL whole blood or two buccal swabs

Container

Lavender-top (EDTA) tube, yellow-top (ACD) tube, or LabCorp buccal swab kit

Storage Instructions

Maintain specimen at room temperature, or refrigerate at 4°C.

Causes for Rejection

Frozen specimen; hemolysis; quantity not sufficient for analysis; improper container; single buccal swab

Clinical Information

References

Barratt DT, Bandak B, Klepstad P, et al. Genetic, pathological and physiological determinants of transdermal fentanyl pharmacokinetics in 620 cancer patients of the EPOS study. Pharmacogenet Genomics. 2014 Apr; 24(4):185-194. 24469018
Birdwell KA, Decker B, Barbarino JM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing. Clin Pharmacol Ther. 2015 Jul; 98(1):19-24. doi: 10.1002/cpt.113. 25801146
Elens L, Becker ML, Haufroid V, et al. Novel CYP3A4 intron 6 single nucleotide polymorphism is associated with simvastatin-mediated cholesterol reduction in the Rotterdam Study. Pharmacogenet Genomics. 2011 Dec; 21(12):861-866. 21946898

LOINC® Map

Order Code Order Code Name Order Loinc Result Code Result Code Name UofM Result LOINC
504155 Cytochrome P450 3A4/3A5 81642-1 504161 3A4 Genotype: 81139-8
504155 Cytochrome P450 3A4/3A5 81642-1 504162 3A4 Metabolic Activity: 51971-0
504155 Cytochrome P450 3A4/3A5 81642-1 504163 3A5 Genotype: 81140-6
504155 Cytochrome P450 3A4/3A5 81642-1 504164 3A5 Metabolic Activity: 79717-5
504155 Cytochrome P450 3A4/3A5 81642-1 504165 Interpretation: 81146-3
504155 Cytochrome P450 3A4/3A5 81642-1 504166 Comments: 77202-0
504155 Cytochrome P450 3A4/3A5 81642-1 504167 CYP3A4/3A5 Information: 62364-5
504155 Cytochrome P450 3A4/3A5 81642-1 504168 References: 75608-0
504155 Cytochrome P450 3A4/3A5 81642-1 000000 Esoterix Informed Consent Req N/A
504155 Cytochrome P450 3A4/3A5 81642-1 504169 Cytochrome P450 3A4/3A5 N/A

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