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Enzyme:CYP2D6: Difference between revisions

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Pharmacogenomics entity page prototype: CYP2D6. First of 10 canonical enzyme pages (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, UGT1A1, TPMT) to be built in Phase 1. Sandboxed at Pharmacopedia:Pharmacogenomics sandbox/ until interface-claude registers the Enzyme: custom namespace; will move to Enzyme:CYP2D6 thereafter. Cites Crews 2021 CPIC opioid guideline (PMID 33387367) + Caudle 2020 CPIC/DPWG CYP2D6 harmonization (PMID 31647186). 0 em-dashes; 16 en-dashes (all in nume...
 
Consolidate enzyme entity page to canonical Pharmacopedia: sandbox location per Mark 2026-05-19. Full retrofitted version: history-first spine, collapsible-sortable substrate table, comprehensive-tables pointer, all PMIDs NCBI-eutils-verified, zero em-dashes. For CYP2D6/CYP3A4/CYP2C19 this replaces the earlier pre-retrofit draft with the full version; for the other 8 enzymes this is the first save at the canonical location. Resolves a cross-session sandbox-location duplication: the User:MDEll...
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== Function and substrate spectrum ==
== 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.
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.<ref name="zanger2013">Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. ''Pharmacology and Therapeutics''. 2013 Apr;138(1):103-141. PMID: 23333322.</ref>


Substrate classes of clinical importance include:
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|Comprehensive substrate and interaction tables]] below for the authoritative maintained resources.


* '''Opioid prodrug activators''': [[Codeine|codeine]] → [[Morphine|morphine]], [[Tramadol|tramadol]] → O-desmethyltramadol (M1), [[Hydrocodone|hydrocodone]] → hydromorphone. Loss-of-function CYP2D6 reduces or abolishes analgesia; gain-of-function increases morphine exposure and respiratory-depression risk.<ref name="cpic-opioid-2021" />
{| class="wikitable sortable mw-collapsible mw-collapsed" style="width:100%;"
* '''Antidepressants''': all tricyclics ([[Amitriptyline|amitriptyline]], [[Nortriptyline|nortriptyline]], [[Imipramine|imipramine]], [[Desipramine|desipramine]], [[Clomipramine|clomipramine]]) and several SSRIs ([[Fluoxetine|fluoxetine]] is itself a substrate as well as an inhibitor; [[Paroxetine|paroxetine]] is a substrate as well as a mechanism-based inhibitor; [[Venlafaxine|venlafaxine]], [[Vortioxetine|vortioxetine]]). CPIC publishes phenotype-specific dosing guidance for the tricyclics and several SSRIs.
|+ style="white-space:nowrap; text-align:left;" | near-complete CYP2D6 substrate table (click to expand)
* '''Antipsychotics''': [[Risperidone|risperidone]], [[Aripiprazole|aripiprazole]], [[Haloperidol|haloperidol]], [[Iloperidone|iloperidone]], [[Brexpiprazole|brexpiprazole]], [[Pimozide|pimozide]]. Pimozide carries an FDA boxed warning regarding CYP2D6 genotype.
! Substrate !! Therapeutic class !! CYP2D6 contribution !! Clinical notes
* '''β-blockers''': [[Metoprolol|metoprolol]] (substantially), [[Carvedilol|carvedilol]], [[Propranolol|propranolol]] (partial). CYP2D6 polymorphism contributes to wide inter-individual variability in β-blockade.
|-
* '''Antiarrhythmics''': [[Flecainide|flecainide]], [[Mexiletine|mexiletine]], propafenone.
| [[Amitriptyline]] || Tricyclic antidepressant || major || CPIC TCA guideline dose adjustment in CYP2D6 PM/UM.
* '''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).
| [[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|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 ==
== Phenotype categories and activity-score system ==
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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.<ref name="cpic-opioid-2021" /><ref name="caudle2020" />
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.<ref name="cpic-opioid-2021" /><ref name="caudle2020" />
== 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.<ref name="pharmgkb2021">Whirl-Carrillo M, Huddart R, Gong L, Sangkuhl K, Thorn CF, Whaley R, Klein TE. An Evidence-Based Framework for Evaluating Pharmacogenomics Knowledge for Personalized Medicine. ''Clinical Pharmacology and Therapeutics''. 2021 Sep;110(3):563-572. PMID: 34216021.</ref> 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.<ref name="zanger2013" />


== See also ==
== See also ==
Retrieved from "https://pharmacopedia.wiki/p/Enzyme:CYP2D6"