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 to 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.

The table below collects the clinically important CYP2D6 substrates with each entry tagged by the contribution CYP2D6 makes to overall clearance (or to bioactivation, where the relevant medicine is a CYP2D6-activated prodrug): major (CYP2D6 is the predominant route), moderate (CYP2D6 contributes meaningfully but other routes carry comparable load), minor (CYP2D6 contributes but other pathways dominate), and partial (one of several substantial routes). The list is curated for clinical relevance and is not exhaustive; see Comprehensive substrate and interaction tables below for the authoritative maintained resources.

near-complete CYP2D6 substrate table (click to expand)

Substrate	Therapeutic class	CYP2D6 contribution	Clinical notes
Amitriptyline	Tricyclic antidepressant	major	CPIC TCA guideline dose adjustment in CYP2D6 PM/UM.
Aripiprazole	Atypical antipsychotic	major	FDA labeling recommends dose reduction in CYP2D6 PMs.
Atomoxetine	ADHD (norepinephrine reuptake inhibitor)	major	CPIC Level A guideline: CYP2D6 PMs require slower titration and reduced maintenance dose.
Brexpiprazole	Atypical antipsychotic	major	FDA labeling: half the standard dose in CYP2D6 PMs.
Carvedilol	Beta blocker	moderate	CYP2D6 polymorphism contributes to variability in beta blockade.
Chlorpheniramine	H1 antihistamine	moderate	Older first-generation antihistamine; mixed CYP2D6 + CYP3A4.
Clomipramine	Tricyclic antidepressant	major	CPIC TCA guideline dose adjustment in CYP2D6 PM/UM.
Clozapine	Atypical antipsychotic	minor	Predominantly CYP1A2; CYP2D6 minor contribution.
Codeine	Opioid analgesic (prodrug)	major	Activation reaction. Converted to morphine by CYP2D6 O-demethylation. PMs derive no analgesia; UMs are at risk of respiratory depression from rapid morphine generation. CPIC strongly recommends against codeine in PMs and UMs.
Desipramine	Tricyclic antidepressant	major	A classic CYP2D6 probe substrate; CPIC TCA guideline dose adjustment.
Dextromethorphan	Antitussive (NMDA antagonist)	major	The standard pharmacological probe substrate for CYP2D6 activity in research studies.
Dihydrocodeine	Opioid analgesic (prodrug)	major	Activation to dihydromorphine; same CYP2D6-dependence pattern as codeine.
Diphenhydramine	H1 antihistamine (first-generation)	moderate	Mixed CYP2D6 + CYP3A4 + non-CYP routes.
Donepezil	Cholinesterase inhibitor (dementia)	moderate	Mixed CYP2D6 + CYP3A4.
Doxepin	Tricyclic antidepressant	major	CPIC TCA guideline dose adjustment in CYP2D6 PM/UM.
Duloxetine	SNRI antidepressant	moderate	Mixed CYP2D6 + CYP1A2; duloxetine is itself a moderate CYP2D6 inhibitor.
Flecainide	Antiarrhythmic (class IC)	major	PMs have substantially elevated plasma flecainide and increased arrhythmic risk.
Fluoxetine	SSRI antidepressant	major	Also a strong CYP2D6 inhibitor with long-half-life inhibitory metabolite (norfluoxetine).
Galantamine	Cholinesterase inhibitor (dementia)	major	PMs have higher exposures.
Haloperidol	Typical antipsychotic	major	PMs have higher plasma haloperidol; extrapyramidal-symptom risk elevated.
Hydrocodone	Opioid analgesic (prodrug)	partial	Activation to hydromorphone is CYP2D6-mediated, but hydrocodone itself has analgesic activity, so CYP2D6 deficiency does not abolish effect.
Iloperidone	Atypical antipsychotic	major	FDA labeling: dose reduction in CYP2D6 PMs.
Imipramine	Tricyclic antidepressant	major	CPIC TCA guideline dose adjustment.
Metoclopramide	Antiemetic / prokinetic	moderate	Mixed CYP2D6 + non-CYP routes.
Metoprolol	Beta blocker	major	PMs have several-fold higher plasma metoprolol; clinically significant variability in beta blockade.
Mexiletine	Antiarrhythmic (class IB)	major	PMs have higher exposures.
Nebivolol	Beta blocker	major	PMs have substantially higher exposures.
Nortriptyline	Tricyclic antidepressant	major	CPIC TCA guideline dose adjustment in CYP2D6 PM/UM.
Olanzapine	Atypical antipsychotic	minor	Predominantly CYP1A2 + glucuronidation; CYP2D6 minor.
Ondansetron	5-HT3 antagonist (antiemetic)	major	CPIC guideline: CYP2D6 UMs may have reduced antiemetic efficacy; consider alternative.
Oxycodone	Opioid analgesic	minor	Has intrinsic mu-opioid activity; CYP2D6 produces oxymorphone (potent metabolite) as a minor route. PMs retain analgesia.
Paroxetine	SSRI antidepressant	major	Substrate AND strong mechanism-based inhibitor (auto-inhibits its own clearance). The mechanism-based component persists for days beyond paroxetine discontinuation.
Perhexiline	Antianginal (rarely prescribed)	major	Catastrophic hepatotoxicity and neuropathy in CYP2D6 PMs; effectively contraindicated without pre-prescription genotyping.
Perphenazine	Typical antipsychotic	major	PMs have higher exposures and increased extrapyramidal-symptom risk.
Pimozide	Typical antipsychotic	major	FDA boxed warning: dose cap in CYP2D6 PMs and avoid co-prescription of CYP2D6 inhibitors because of QT-prolongation risk.
Promethazine	H1 antihistamine / antiemetic (first-generation)	moderate	Mixed CYP2D6 + non-CYP.
Propafenone	Antiarrhythmic (class IC)	major	PMs have substantially higher plasma propafenone and a different metabolite profile (no 5-OH-propafenone); the active-metabolite contribution changes the pharmacology.
Propranolol	Beta blocker	moderate	Mixed CYP2D6 + CYP1A2 + CYP2C19 routes.
Risperidone	Atypical antipsychotic	major	Activation reaction. Converts risperidone to 9-OH-risperidone (paliperidone), the active metabolite. PMs have higher parent-compound and lower active-metabolite exposure; clinical net effect is modest because both are active at the same receptors.
Tamoxifen	Anti-estrogen (breast cancer)	major	Activation reaction. CYP2D6 converts tamoxifen to endoxifen, the most potent active metabolite. PMs may have reduced antitumor efficacy; the magnitude of clinical effect in modern adjuvant regimens has been debated through repeated trial cohorts.
Thioridazine	Typical antipsychotic	major	PMs have substantially higher exposures and QT-prolongation risk; rarely prescribed today partly because of this.
Timolol	Beta blocker (including ophthalmic)	major	Even systemic absorption from ophthalmic timolol can produce clinically meaningful beta blockade in CYP2D6 PMs.
Tolterodine	Antimuscarinic (overactive bladder)	major	PMs have higher exposures; FDA labeling references CYP2D6 status.
Tramadol	Opioid analgesic (prodrug)	major	Activation reaction. Converted to O-desmethyltramadol (M1) by CYP2D6, the active mu-opioid metabolite. Same PM/UM analgesic-effect and respiratory-depression pattern as codeine. CPIC opioid guideline addresses both.
Venlafaxine	SNRI antidepressant	major	Activation reaction. Converts venlafaxine to O-desmethylvenlafaxine (desvenlafaxine), which is itself a marketed antidepressant.
Vortioxetine	Multimodal serotonergic antidepressant	major	PMs require dose reduction per FDA labeling.

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.

Comprehensive substrate and interaction tables

The substrate and interaction tables on this page are curated for clinical relevance, not for completeness. Three authoritative external resources maintain comprehensive lists of CYP2D6 substrates, inhibitors, and inducers, and the wiki recommends them to any reader who needs an exhaustive look-up:

• Flockhart Cytochrome P450 Drug Interaction Table, maintained by the Department of Medicine at Indiana University School of Medicine. The most widely cited clinical-reference cytochrome P450 table; substrate-, inhibitor-, and inducer-tiered, updated regularly. Available at https://drug-interactions.medicine.iu.edu/.
• U.S. Food and Drug Administration Drug Development and Drug Interactions Table, the regulatory-grade list FDA uses for labeling and clinical-trial design decisions. Smaller than Flockhart but every entry is FDA-vetted. Available via the FDA Center for Drug Evaluation and Research clinical drug interaction page.
• PharmGKB, the pharmacogenomics knowledge base hosted at Stanford University; the CYP2D6 gene page indexes substrate-, inhibitor-, and inducer-relationships with their underlying primary literature, and links each gene-drug pair to the CPIC dosing guideline where one exists. Available at https://www.pharmgkb.org/.

For a comprehensive review of CYP2D6 (and the rest of the human cytochrome P450 family) covering regulation, polymorphism, and substrate spectrum in detail, the Zanger and Schwab 2013 review in Pharmacology and Therapeutics remains the standard reference.

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)