Enzyme:CYP2D6

CYP2D6 (cytochrome P450 2D6) is a hepatic drug-metabolizing enzyme of the cytochrome P450 superfamily. It is encoded by the CYP2D6 gene on chromosome 22q13.2 and accounts for roughly 2–4% of total hepatic CYP protein, yet metabolizes an outsized fraction of the medicines in clinical use (estimates range from 20 to 25% of all prescribed drugs touch CYP2D6 in some way). It is the most extensively polymorphic of the human CYP enzymes, with more than 100 named star-allele variants ranging from complete loss of function to gain-of-function gene duplications. Because of this polymorphism and the steepness of the dose-response relationship for several CYP2D6-dependent medicines, CYP2D6 is the most clinically consequential single pharmacogenomic locus in routine prescribing.

Function and substrate spectrum

CYP2D6 catalyzes O-dealkylation, N-dealkylation, hydroxylation, and oxidation of a wide range of lipophilic substrates that share a basic nitrogen 5–7 Å from an aromatic carbon. The enzyme is uninducible by classical pharmacological inducers (rifampin, carbamazepine, phenobarbital), which distinguishes it from CYP3A4 and CYP1A2 and means that CYP2D6 inhibition cannot be overcome by attempting to upregulate the enzyme.

Substrate classes of clinical importance include:

• Opioid prodrug activators: codeine → morphine, tramadol → O-desmethyltramadol (M1), hydrocodone → hydromorphone. Loss-of-function CYP2D6 reduces or abolishes analgesia; gain-of-function increases morphine exposure and respiratory-depression risk.
• Antidepressants: all tricyclics (amitriptyline, nortriptyline, imipramine, desipramine, clomipramine) and several SSRIs (fluoxetine is itself a substrate as well as an inhibitor; paroxetine is a substrate as well as a mechanism-based inhibitor; venlafaxine, vortioxetine). CPIC publishes phenotype-specific dosing guidance for the tricyclics and several SSRIs.
• Antipsychotics: risperidone, aripiprazole, haloperidol, iloperidone, brexpiprazole, pimozide. Pimozide carries an FDA boxed warning regarding CYP2D6 genotype.
• β-blockers: metoprolol (substantially), carvedilol, propranolol (partial). CYP2D6 polymorphism contributes to wide inter-individual variability in β-blockade.
• Antiarrhythmics: flecainide, mexiletine, propafenone.
• Tamoxifen: metabolized to endoxifen, the clinically active metabolite; CYP2D6 phenotype influences tamoxifen efficacy in breast cancer treatment, though the magnitude of effect in modern adjuvant regimens has been debated.
• Others: atomoxetine (a CPIC Level A example for ADHD prescribing), dextromethorphan, perhexiline (catastrophic hepatotoxicity in poor metabolizers).

Phenotype categories and activity-score system

CYP2D6 phenotype is assigned by summing the activity-score values of an individual's two CYP2D6 alleles. The harmonized 2019 consensus assigns each allele a value from 0 (no function) to 2.0 (increased function for some star alleles; alleles in tandem duplications add proportionally).

Phenotype	Abbreviation	Activity score	Frequency (varies by ancestry)
Poor metabolizer	PM	0	5–10% (European), 1–2% (East Asian), 3–8% (African)
Intermediate metabolizer	IM	>0 to ≤1.25	10–17% (European), 30–50% (East Asian), 20–35% (African)
Normal metabolizer	NM	>1.25 to ≤2.25	65–80% (European), 45–65% (East Asian), 50–70% (African)
Ultrarapid metabolizer	UM	>2.25	1–5% (European), <1% (East Asian), 1–10% (African), up to 28% (Ethiopian, some North African and Middle Eastern populations)

The activity-score scheme superseded the older categorical "extensive metabolizer" (EM, now called NM) terminology in the 2019 harmonization between CPIC and the Dutch Pharmacogenetics Working Group (DPWG). The relabeling reflects that "extensive" was being read by clinicians as "above-normal" when it actually meant "typical".

Major star alleles

The full catalog of named alleles is maintained at PharmVar (formerly the Human CYP Allele Nomenclature Committee). Clinically the most-encountered are:

• *1, reference, fully functional (activity 1.0)
• *2, fully functional or near-normal (activity 1.0)
• *3, frameshift, no function (activity 0)
• *4, splice variant, the most common no-function allele in European-ancestry populations (activity 0)
• *5, whole-gene deletion (activity 0)
• *6, frameshift, no function (activity 0)
• *10, decreased function (activity 0.25); the most common decreased-function allele in East Asian populations
• *17, decreased function (activity 0.5); most common in African-ancestry populations
• *41, decreased function (activity 0.25)
• *xN, gene duplication of any allele; an *1xN duplication adds 1.0 per extra copy of *1, producing UM phenotypes

Inhibitors

CYP2D6 inhibition by a co-prescribed medicine produces a "phenocopy" of CYP2D6 deficiency: an individual with the genotype of a normal metabolizer behaves as an intermediate or poor metabolizer for as long as the inhibitor is present. The strength and kinetic class of inhibition determine the magnitude and duration of the effect.

Strong reversible-competitive inhibitors include fluoxetine (plus its long-half-life metabolite norfluoxetine), bupropion, quinidine. Strong mechanism-based inhibitors include paroxetine (mechanism-based component contributes to the slow recovery of CYP2D6 activity after discontinuation) and terbinafine (covalent inactivation). Moderate inhibitors include duloxetine, sertraline (only at higher doses), cinacalcet.

The clinical relevance of CYP2D6 inhibition is greatest for substrates whose elimination depends predominantly on CYP2D6 (no redundant pathway) and whose dose-response sits on a steep part of the curve. Codeine and tramadol are the textbook cases; metoprolol and tamoxifen are subtler.

Inducers

CYP2D6 is essentially non-inducible by the classical PXR/CAR-mediated induction pathway. Rifampin, carbamazepine, phenobarbital, and St John's Wort, all potent inducers of CYP3A4 and other CYPs, have negligible effect on CYP2D6 expression. This is clinically important because it means CYP2D6-substrate dosing cannot be rescued by pharmacological induction; if a medicine fails because of CYP2D6 inhibition or because the patient is a poor metabolizer, the answer is to switch the offending inhibitor or switch to an alternative substrate, not to wait for tolerance to develop.

Clinical implications, summary

For any medicine that depends materially on CYP2D6 for activation or elimination:

• Known PM phenotype: avoid prodrugs that require CYP2D6 activation (no analgesia from codeine/tramadol); reduce starting dose of substrates eliminated by CYP2D6 (typically 50% reduction for tricyclic antidepressants).
• Known UM phenotype: avoid codeine, tramadol, and other CYP2D6-activated prodrugs (toxicity risk from rapid morphine generation); standard or slightly increased dosing for substrates eliminated by CYP2D6.
• Standard genotype + strong CYP2D6 inhibitor co-prescribed: treat as phenocopy intermediate or poor metabolizer for the duration of the inhibitor's effect. Note that fluoxetine's effect persists 4–6 weeks beyond discontinuation because of norfluoxetine (half-life 7–15 days), and paroxetine's mechanism-based inhibition recovers over the synthesis half-life of CYP2D6 (~24–48 hours per enzyme copy) rather than over paroxetine's elimination half-life.

CPIC publishes phenotype-specific dosing guidance for codeine/tramadol, atomoxetine, ondansetron and tropisetron, several tricyclic antidepressants, several SSRIs, tamoxifen, pimozide, and others; the full set is maintained at clinpgx.org.

See also

• Phenotype:CYP2D6 poor metabolizer
• Phenotype:CYP2D6 intermediate metabolizer
• Phenotype:CYP2D6 normal metabolizer
• Phenotype:CYP2D6 ultrarapid metabolizer
• Enzyme:CYP3A4, Enzyme:CYP2C19, Enzyme:CYP2C9
• Codeine, Tramadol, Tamoxifen, Fluoxetine, Paroxetine (canonical clinical examples)