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. CYP2B6 is wholly or partially responsible for the metabolism of several commonly prescribed drugs.

The CYP2B6 gene is highly variable with over 38 named alleles. The gene can have multiple sequence variations. Alleles thought to have an impact upon CYP2B6 enzyme function at the time that this test was developed are included in this test (see Table). Individuals without a detectable gene alteration will be reported as CYP2B6*1/*1, but it is possible that these individuals harbor unknown variants that may impact metabolism. In addition, some individuals have genes that are hybrids of CYP2B6 and the CYP2B7 pseudogene. The frequency of these hybrids is unknown, and this assay does not test for these hybrids.

Phenotyping is derived from the Pharmacogene Variation Consortium website(1), an exhaustive review of the CYP2B6 literature, the Clinical Pharmacogenetics Implementation Consortium website(2), and published guidelines.(3) CYP2B6 genotype results are used to predict metabolizer phenotypes. A CYP2B6 phenotype is predicted based upon the number of functional, partially functional, and nonfunctional alleles present in a sample. In rare instances where alleles with unknown function are present in a homozygous or compound heterozygous state, an unknown phenotype occurs. It should be noted that other laboratories may use different phenotype prediction methods as there is no consensus on this at this time. However, the method used here represents the findings of the majority of literature available.

Several medications act as substrates of CYP2B6. CYP2B6-metabolized medications with the highest quality of data for the impact of various CYP2B6 alleles on metabolism are:

-Bupropion

-Efavirenz

-Ketamine

-Methadone

-Nevirapine

Other enzymes may be involved in the metabolism of these drugs. For example, bupropion is also metabolized by CYP2D6. Efavirenz is also metabolized by CYP2A6, although CYP2B6 is the major metabolizing enzyme. Ketamine is also metabolized by CYP2A6, and nevirapine is also metabolized by CYP3A4 and CYP3A5. CYP2A6 testing is not available clinically at the time this document was written, but CYP2D6 (2D6Q / Cytochrome P450 2D6 Comprehensive Cascade, Varies), CYP3A4 (3A4Q / Cytochrome P450 3A4 Genotype, Varies), and CYP3A5 (3A5Q / Cytochrome P450 CYP3A5 Genotype, Varies) testing is available.

There is a variable degree of substrate specificity exhibited by CYP2B6 alleles on these medications. This means that the same allele (ie, *6) may not metabolize all substrates at exactly the same rate.

Drugs that are metabolized by CYP2B6 may require dosage adjustment based on the individual patient's genotype. For example, patients who are poor metabolizers may require much lower than usual doses to achieve optimal response in the case of drugs that are inactivated by the CYP2B6 enzyme. Alternatively, patients who are ultrarapid metabolizers may benefit from increased doses in the case of drugs that are inactivated by CYP2B6 enzyme. In the absence of clear guidance from the FDA on dosing for various metabolizer phenotypes, patients with either ultrarapid or poor metabolism may benefit by switching to comparable alternate medications that are not primarily metabolized by CYP2B6 or by therapeutic drug monitoring where applicable.

Table. Enzyme Activity of Individual Star Alleles