Clinical Information

The cytochrome P450 (CYP) family of enzymes is a group of oxidative/dealkylating enzymes localized in the microsomes of many tissues including the intestines and liver. One of the CYP enzymes, CYP2D6, is wholly or partially responsible for the metabolism of many commonly prescribed drugs.

The CYP2D6 gene is highly variable with over 100 named alleles. The gene may be deleted, duplicated, and multiplied, and can have multiple sequence variations. In addition, some individuals have genes that are hybrids of CYP2D6 and the CYP2D7 pseudogene. Some individuals have CYP2D6 variants that result in synthesis of an enzyme with decreased or absent catalytic activity. These individuals may process CYP2D6-metabolized medications more slowly. CYP2D6 duplications and multiplications involving active alleles may result in ultrarapid metabolism of CYP2D6-metabolized drugs. CYP2D6 genotype results are used to predict metabolizer phenotypes.(See Table 1)

Table 1. Enzyme Activity of Individual Star Alleles

CYP2D6 phenotype is predicted based upon the number of functional, partially functional, and nonfunctional alleles present in a sample.

Phenotyping is derived from the Pharmacogene Variation Consortium website (1), the Clinical Pharmacogenetics Implementation Consortium website (2), published guidelines (3-8), and an exhaustive review of the CYP2D6 literature (9-10).

There are instances where a precise phenotype prediction is not possible, and in these instances, a range of possible phenotypes will be given. Individuals without a detectable gene alteration will have the predicted phenotype of an extensive drug metabolizer and are designated as CYP2D6*1/*1.

Drugs that are metabolized through CYP2D6 may require dosage adjustment based on the individual patient's genotype. Patients who are poor metabolizers may require lower than usual doses to achieve optimal response in the case of drugs that are inactivated by the CYP2D6 enzyme and higher than usual doses in the case of drugs that are activated by CYP2D6 enzyme. Alternatively, patients who are ultrarapid metabolizers may benefit from increased doses in the case of drugs that are inactivated by CYP2D6 enzyme and lower doses in the case of drugs that are activated by CYP2D6. In the absence of clear guidance from FDA on dosing for various metabolizer phenotypes, patients with either ultrarapid or poor metabolism may benefit by switching to comparable alternate medications not primarily metabolized by CYP2D6 or by therapeutic drug monitoring where applicable.

Overall, this test provides a comprehensive CYP2D6 genotype result for patients, ensuring a more accurate phenotype prediction. This assay has clinical significance for patients taking or considering medications activated (eg, codeine, tramadol, and tamoxifen) or inactivated (eg, antidepressants and antipsychotics) by the CYP2D6 enzyme.

Sequential tier testing associated with this test will be initiated until the least ambiguous phenotype possible is determined.