CYP2D6

CYP2D6, or cytochrome P450 2D6, is a liver enzyme encoded by the CYP2D6 gene in humans. It is part of the cytochrome P450 family and participates in phase I drug metabolism, performing oxidative transformations on a wide range of foreign and endogenous compounds. The enzyme metabolizes a substantial portion of prescription drugs, estimated at about 20–25%, including many antidepressants, antipsychotics, beta blockers, antiarrhythmics, various opioids, and the prodrug tamoxifen.

Genetic variation in CYP2D6 is extensive and defines distinct metabolic phenotypes. Allelic differences determine enzyme activity: some alleles abolish function, others reduce function, and gene duplications can increase activity. Individuals are commonly categorized as poor metabolizers (PM), intermediate metabolizers (IM), extensive/normal metabolizers (EM), or ultrarapid metabolizers (UM). Copy number variation is common, and the distribution of these phenotypes varies across populations.

Clinical implications are significant for drugs that rely on CYP2D6. Poor metabolizers may experience reduced efficacy with certain prodrugs or altered drug levels, while ultrarapid metabolizers may convert drugs to active or toxic metabolites too quickly. For example, codeine is activated to morphine by CYP2D6, so PMs may obtain little analgesia, whereas ultrarapid metabolizers may be at risk of morphine toxicity. Tamoxifen activation to endoxifen can also be affected, potentially influencing treatment outcomes in some patients.

Pharmacogenetic testing for CYP2D6 can guide drug selection and dosing for specific medications. Guidelines from CPIC and others provide genotype-based recommendations. Expression is highest in the liver, with intestinal expression contributing to first-pass metabolism; drug interactions and other genetic factors can modulate activity.