Cytochrome P450 Genotyping

The cytochrome P450 (CYP) isozymes 2B6, 2C19, 2C8, 2C9, 2D6, 3A4, and 3A5 are involved in the metabolism of many drugs. Variants in the genes that code for these enzymes may influence pharmacokinetics of the respective medications, and therefore may predict or explain nonstandard dose requirements, therapeutic failure, or adverse reactions.

For more information on pharmacogenetic testing, refer to the ARUP Consult Germline Pharmacogenetics - PGx topic.

Treatment Issues

• The actual metabolic phenotype of a drug metabolizing enzyme is subject to drug-drug interactions, clinical factors, and other nongenetic factors.
• Therapeutic drug monitoring and/or metabolic ratios may be useful for evaluating the pharmacokinetics of a particular drug for a particular patient.
  • Refer to the ARUP Laboratory Test Directory for a list of available drug-gene specific testing (search by test name or number).
• The Clinical Pharmacogenetics Implementation Consortium (CPIC)  and the Food and Drug Administration (FDA)  have published clinical associations and dosing guidelines involving CYP genotypes.

Genetics

Genes

CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2C rs12777823, CYP2D6, CYP3A4, CYP3A5

Inheritance

Autosomal codominant

Variants Tested

Variants or groups of variants are classified as “star” (*) alleles, that are associated with predicted enzyme function, based on international consensus nomenclature. However, not all variants on a chromosome/allele are interrogated and assumptions about phase are made, as shown below. More details about nomenclature, allele frequencies and phenotype predictions are available at PharmVar  or PharmGKB. 

Results

• Genetic variant(s) detected: alleles detected are reported. The combination of alleles detected or diplotype is used to predict metabolizer phenotype, and in the case of CYP2D6, the activity score. Phenotype predictions are subject to change as the scientific and clinical evidence evolves.
• Samples where CYP2D6 copy number testing reveals a duplication and where there are two alleles of different activity scores, will be reflexed to LR-PCR for additional testing to reveal which allele is duplicated.
• No variants detected is predictive of *1 functional alleles.
• Functional variants without clinical indication or impact on clinical management may not be reported.

Limitations

• Only the targeted genetic variants will be detected by this panel. Assumptions about phase and content are made to assign alleles.
• Diagnostic errors can occur due to rare sequence variations.
• A combination of the CYP2D6*5 (gene deletion) and a CYP2D6 gene duplication cannot be specifically identified; however, this combination is not expected to adversely affect the phenotype prediction.
• The assay used to detect the CYP2D6*40 allele cannot distinguish between insertions of one or two copies; it also cannot distinguish between heterozygous and homozygous mutant samples due to unavoidable cross reactivity with the wild type sequence. Additional assays will be used to help differentiate the CYP2D6*40 allele from other CYP2D6 star alleles.
• Risk of therapeutic failure or adverse reactions with gene substrates may be affected by genetic and nongenetic factors that are not detected by this test.
• The test result does not replace the need for therapeutic drug or clinical monitoring.