MDElliottMD: Add scope="col" to the data-table column headers for screen-reader association (ADA audit M5; designer-claude 2026-05-22)

2026-05-22T16:53:06Z

Add scope="col" to the data-table column headers for screen-reader association (ADA audit M5; designer-claude 2026-05-22)

← Older revision		Revision as of 16:53, 22 May 2026
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	{\| class="wikitable sortable mw-collapsible mw-collapsed" style="width:100%;"		{\| class="wikitable sortable mw-collapsible mw-collapsed" style="width:100%;"
	\|+ style="white-space:nowrap; text-align:left;" \| near-complete CYP2C19 substrate table (click to expand)		\|+ style="white-space:nowrap; text-align:left;" \| near-complete CYP2C19 substrate table (click to expand)
	! Substrate !! Therapeutic class !! CYP2C19 contribution !! Clinical notes		! scope="col" \| Substrate !! scope="col" \| Therapeutic class !! scope="col" \| CYP2C19 contribution !! scope="col" \| Clinical notes
	\|-		\|-
	\| [[Amitriptyline]] \|\| Tricyclic antidepressant \|\| partial \|\| N-demethylation to nortriptyline is partly CYP2C19; CYP2D6 dominates the hydroxylation step.		\| [[Amitriptyline]] \|\| Tricyclic antidepressant \|\| partial \|\| N-demethylation to nortriptyline is partly CYP2C19; CYP2D6 dominates the hydroxylation step.
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	{\| class="wikitable"		{\| class="wikitable"
	! Phenotype !! Abbreviation !! Diplotype (typical) !! Approximate frequency		! scope="col" \| Phenotype !! scope="col" \| Abbreviation !! scope="col" \| Diplotype (typical) !! scope="col" \| Approximate frequency
	\|-		\|-
	\| [[Phenotype:CYP2C19 poor metabolizer\|Poor metabolizer]] \|\| PM \|\| two no-function alleles \|\| 2–5% European, 13–23% East Asian, 4% African		\| [[Phenotype:CYP2C19 poor metabolizer\|Poor metabolizer]] \|\| PM \|\| two no-function alleles \|\| 2–5% European, 13–23% East Asian, 4% African

MDElliottMD: MDElliottMD moved page Pharmacopedia:Pharmacogenomics sandbox/Enzyme CYP2C19 to Enzyme:CYP2C19: Migrate enzyme entity pages from Pharmacogenomics sandbox to the new Enzyme: namespace

2026-05-22T02:55:06Z

MDElliottMD moved page Pharmacopedia:Pharmacogenomics sandbox/Enzyme CYP2C19 to Enzyme:CYP2C19: Migrate enzyme entity pages from Pharmacogenomics sandbox to the new Enzyme: namespace

← Older revision	Revision as of 02:55, 22 May 2026
(No difference)

MDElliottMD: 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...

2026-05-19T22:39:06Z

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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MDElliottMD: Pharmacogenomics entity page: CYP2C19. Three CPIC Level A indications (clopidogrel + PPIs + SSRIs/voriconazole). Five-phenotype classification PM/IM/NM/RM/UM driven by 2 / 3 / *17 alleles; ancestry-frequency variation called out. Clopidogrel prodrug-activation story; PPI dose-by-phenotype; SSRI QT-prolongation in PMs. 9 inline cites across 4 PMID-verified refs: Wilkinson 2005 NEJM (PMID 15917386), Lee/Luzum 2022 CPIC clopidogrel (PMID 35034351), Lima 2021 CPIC PPI (PMID 32770672), Bousman 2...

2026-05-19T16:43:03Z

Pharmacogenomics entity page: CYP2C19. Three CPIC Level A indications (clopidogrel + PPIs + SSRIs/voriconazole). Five-phenotype classification PM/IM/NM/RM/UM driven by *2 / *3 / *17 alleles; ancestry-frequency variation called out. Clopidogrel prodrug-activation story; PPI dose-by-phenotype; SSRI QT-prolongation in PMs. 9 inline cites across 4 PMID-verified refs: Wilkinson 2005 NEJM (PMID 15917386), Lee/Luzum 2022 CPIC clopidogrel (PMID 35034351), Lima 2021 CPIC PPI (PMID 32770672), Bousman 2...

New page

'''CYP2C19''' (cytochrome P450 2C19) is a hepatic drug-metabolizing enzyme whose genetic polymorphism is the most clinically actionable in routine prescribing after [[Enzyme:CYP2D6|CYP2D6]]. It is encoded by the ''CYP2C19'' gene on chromosome 10q23.33 and accounts for roughly 5 to 10% of total hepatic CYP protein. Three areas of medicine sit squarely on its activity: the antiplatelet [[Clopidogrel|clopidogrel]] (a prodrug that requires CYP2C19 to be activated to its working form), the proton pump inhibitors used to suppress gastric acid, and several of the SSRI antidepressants and the antifungal voriconazole. Population frequency of the poor-metabolizer phenotype varies markedly by ancestry, which has clinical and ethical implications the wiki returns to below.<ref name="wilkinson2005">Wilkinson GR. Drug metabolism and variability among patients in drug response. ''New England Journal of Medicine''. 2005 May 26;352(21):2211-2221. PMID: 15917386.</ref>

== Function and substrate spectrum ==
CYP2C19 catalyzes hydroxylation and dealkylation of an unusually focused set of substrates, in marked contrast to the catholic substrate spectrum of [[Enzyme:CYP3A4|CYP3A4]]. The substrates that matter most in current practice:

* '''[[Clopidogrel|Clopidogrel]]''' (Plavix). The antiplatelet effect of clopidogrel depends on a two-step bioactivation, the second of which is performed by CYP2C19, converting the parent compound to the thiol metabolite that covalently inactivates the platelet P2Y12 receptor. Poor metabolizers generate substantially less of the active metabolite and obtain less antiplatelet effect, which translates clinically into higher rates of stent thrombosis and major adverse cardiovascular events after percutaneous coronary intervention. CPIC recommends alternative antiplatelet therapy (prasugrel or ticagrelor) for poor and intermediate metabolizers in the post-PCI setting; the recommendation carries CPIC's strongest classification.<ref name="cpic-clopidogrel-2022">Lee CR, Luzum JA, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 Genotype and Clopidogrel Therapy: 2022 Update. ''Clinical Pharmacology and Therapeutics''. 2022 Nov;112(5):959-967. PMID: 35034351.</ref> The FDA has carried a boxed warning on clopidogrel's diminished effectiveness in CYP2C19 poor metabolizers since 2010.
* '''Proton pump inhibitors''': [[Omeprazole|omeprazole]], esomeprazole, pantoprazole, lansoprazole, dexlansoprazole are all cleared predominantly by CYP2C19 (rabeprazole less so, since it relies more heavily on a non-enzymatic pathway). Poor metabolizers reach higher plasma concentrations and have better acid suppression at standard doses, while rapid and ultrarapid metabolizers may underrespond. CPIC publishes phenotype-specific dosing guidance, recommending dose increases in rapid and ultrarapid metabolizers and consideration of dose decreases or alternative agents in poor metabolizers, especially during long-term therapy where exposure-related side effects accumulate.<ref name="cpic-ppi-2021">Lima JJ, Thomas CD, Barbarino J, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C19 and Proton Pump Inhibitor Dosing. ''Clinical Pharmacology and Therapeutics''. 2021 Jun;109(6):1417-1423. PMID: 32770672.</ref>
* '''SSRIs''': [[Citalopram|citalopram]], [[Escitalopram|escitalopram]], and to a smaller degree [[Sertraline|sertraline]] are CYP2C19 substrates. Poor metabolizers have higher exposures and a meaningfully elevated risk of QT-interval prolongation on citalopram and escitalopram; CPIC recommends a 50% starting-dose reduction or selection of an alternative antidepressant for poor metabolizers, and consideration of an alternative for ultrarapid metabolizers (in whom subtherapeutic exposures may compromise efficacy).<ref name="cpic-ssri-2023">Bousman CA, Stevenson JM, Ramsey LB, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants. ''Clinical Pharmacology and Therapeutics''. 2023 Jul;114(1):51-68. PMID: 37032427.</ref>
* '''Voriconazole''': poor metabolizers have substantially higher plasma exposures and an increased risk of hepatotoxicity; ultrarapid metabolizers have subtherapeutic exposures and risk treatment failure. Therapeutic drug monitoring is the usual clinical lever, but CYP2C19 genotype can pre-emptively guide the starting dose.
* '''Other substrates of interest''': diazepam (the N-demethylation step), phenytoin (a partial pathway alongside CYP2C9), the tricyclic antidepressants (partial), the antimalarial proguanil (which CYP2C19 activates to cycloguanil).

== Phenotype categories ==
The harmonized CPIC + DPWG phenotype-translation table for CYP2C19 distinguishes five categories rather than the four used for CYP2D6, reflecting the importance of the gain-of-function ''*17'' allele.<ref name="cpic-clopidogrel-2022" />

{| class="wikitable"
! Phenotype !! Abbreviation !! Diplotype (typical) !! Approximate frequency
|-
| [[Phenotype:CYP2C19 poor metabolizer|Poor metabolizer]] || PM || two no-function alleles || 2–5% European, 13–23% East Asian, 4% African
|-
| [[Phenotype:CYP2C19 intermediate metabolizer|Intermediate metabolizer]] || IM || one no-function + one normal-function (or *2/*17, *3/*17, etc.) || 24–36% (varies by ancestry)
|-
| [[Phenotype:CYP2C19 normal metabolizer|Normal metabolizer]] || NM || two normal-function alleles (*1/*1) || 35–45%
|-
| [[Phenotype:CYP2C19 rapid metabolizer|Rapid metabolizer]] || RM || one normal-function + one increased-function (*1/*17) || 18–26% European, lower elsewhere
|-
| [[Phenotype:CYP2C19 ultrarapid metabolizer|Ultrarapid metabolizer]] || UM || two increased-function alleles (*17/*17) || 2–5% European, very rare in East Asian populations
|}

The PM frequency variation by ancestry has practical consequences. In East Asian populations roughly one in five patients prescribed clopidogrel will be a CYP2C19 PM with diminished antiplatelet response, a public-health-scale signal that has driven routine pre-PCI genotyping in some health systems. In European-ancestry populations PMs are uncommon but RMs and UMs (driven by the *17 allele) are common enough that the gain-of-function tail of the distribution matters for the PPI and SSRI guidelines.

== Major star alleles ==
The full allele catalog is maintained at PharmVar. The clinically dominant ones:

* '''*1''', reference, fully functional (activity 1.0)
* '''*2''' (rs4244285, c.681G>A, splice-defect), no function (activity 0). The most common loss-of-function allele worldwide. Frequency roughly 15% in European-ancestry, 25 to 30% in East Asian, 17% in African-ancestry populations.
* '''*3''' (rs4986893, c.636G>A, premature stop), no function (activity 0). Largely an East Asian allele, frequency around 5%, rare elsewhere.
* '''*4''', '''*5''', '''*6''', '''*7''', '''*8''', other rare no-function variants catalogued at PharmVar.
* '''*17''' (rs12248560, c.-806C>T, promoter TATA-box variant), increased function. Increases transcription and produces a roughly 1.5-fold rise in enzyme activity. Frequency roughly 21% in European-ancestry, 18% in African-ancestry, 4% in East Asian populations. The driver of the Rapid and Ultrarapid metabolizer phenotypes.

A diplotype like *1/*2 produces an intermediate metabolizer; *2/*2 produces a poor metabolizer; *1/*17 a rapid metabolizer; *17/*17 an ultrarapid metabolizer. The *2/*17 combination is treated as intermediate per the current consensus, because the loss-of-function effect of *2 outweighs the gain-of-function effect of *17 at the diplotype level.

== Inhibitors ==
CYP2C19 inhibition produces phenocopy poor or intermediate metabolism for the duration of the inhibitor's effect. Strong inhibitors of clinical relevance:

* '''Omeprazole''' and '''esomeprazole''', moderate to strong inhibitors (which also happen to be CYP2C19 substrates themselves, since they self-inhibit at therapeutic exposures). This produces the awkward situation of a patient on a PPI plus clopidogrel: PPIs raise omeprazole exposure (good for acid suppression) but reduce clopidogrel activation (bad for antiplatelet effect). Pantoprazole is a weaker inhibitor and is generally preferred as the PPI co-prescribed with clopidogrel when one is needed.
* '''[[Fluvoxamine|Fluvoxamine]]''', a strong CYP2C19 inhibitor (and a strong CYP1A2 inhibitor as well). Substantial clopidogrel-effect attenuation in healthy-volunteer studies.
* '''[[Fluoxetine|Fluoxetine]]''', moderate to strong inhibitor, with the same long inhibition tail (4 to 6 weeks after discontinuation) as it has at CYP2D6 because of norfluoxetine.
* '''[[Modafinil|Modafinil]]''', moderate inhibitor.
* '''[[Ticlopidine|Ticlopidine]]''', strong inhibitor (historically used as an antiplatelet itself; the irony of an antiplatelet that inhibits the activation of a different antiplatelet is part of why ticlopidine has fallen out of use).

== Inducers ==
CYP2C19 is inducible by the same PXR/CAR-mediated pathway that induces [[Enzyme:CYP3A4|CYP3A4]], though the magnitude of induction is generally smaller. '''[[Rifampin|Rifampin]]''' is the canonical strong inducer, reducing exposures of CYP2C19 substrates by roughly 50 to 80%. Other inducers include '''[[Carbamazepine|carbamazepine]]''', '''[[Phenytoin|phenytoin]]''' (which is also a substrate, producing autoinduction), '''ritonavir''' at chronic dosing, and '''St John's Wort'''. The slow-on / slow-off kinetic profile that characterizes CYP3A4 induction applies here too, and the window after discontinuing an inducer can produce rising substrate exposures over 1 to 3 weeks.

== Clinical implications, summary ==
For any medicine that depends materially on CYP2C19 for activation or clearance:

* '''Known PM phenotype''': avoid prodrugs that require CYP2C19 activation ([[Clopidogrel|clopidogrel]] should be replaced with prasugrel or ticagrelor in the post-PCI setting). Reduce starting dose by 50% for CYP2C19-cleared agents prone to exposure-related toxicity (citalopram, escitalopram). Consider therapeutic drug monitoring for voriconazole.<ref name="cpic-clopidogrel-2022" /><ref name="cpic-ssri-2023" />
* '''Known UM phenotype''': anticipate undertreatment with prodrugs activated by other CYPs (less of a concern for clopidogrel itself, since UM amplifies activation), and with substrates whose clinical effect depends on exposure (PPIs may underwork; voriconazole levels may be subtherapeutic; some SSRIs may be ineffective). CPIC recommends dose increases for PPIs and alternative-agent consideration for SSRIs in this phenotype.<ref name="cpic-ppi-2021" /><ref name="cpic-ssri-2023" />
* '''Standard genotype + strong CYP2C19 inhibitor co-prescribed''' (especially fluvoxamine, fluoxetine, or omeprazole): treat as phenocopy intermediate or poor metabolizer for the duration of the inhibitor's effect. Watch the clopidogrel co-prescription specifically; switch to pantoprazole or H2-blocker if a PPI is needed.
* '''Pre-prescription genotyping''': increasingly routine before clopidogrel initiation in cardiology, especially in health systems serving populations with high PM frequency. Less routine for the PPI and SSRI indications, where alternatives are inexpensive and therapeutic-drug-monitoring substitutes are available.

== See also ==
* [[Phenotype:CYP2C19 poor metabolizer]]
* [[Phenotype:CYP2C19 intermediate metabolizer]]
* [[Phenotype:CYP2C19 normal metabolizer]]
* [[Phenotype:CYP2C19 rapid metabolizer]]
* [[Phenotype:CYP2C19 ultrarapid metabolizer]]
* [[Enzyme:CYP2D6]], [[Enzyme:CYP3A4]], [[Enzyme:CYP2C9]], [[Enzyme:CYP1A2]], [[Enzyme:CYP2B6]]
* [[Clopidogrel]], [[Omeprazole]], [[Escitalopram]], voriconazole (canonical clinical examples)
* [[Fluvoxamine]], [[Fluoxetine]] (canonical inhibitor examples)
* [[Rifampin]] (canonical inducer example)
* [[:Category:Drug-metabolizing enzymes]]

== References ==

<references/>

[[Category:Drug-metabolizing enzymes]]
[[Category:Pharmacogenomics]]

Enzyme:CYP2C19 - Revision history

MDElliottMD: Add scope="col" to the data-table column headers for screen-reader association (ADA audit M5; designer-claude 2026-05-22)

MDElliottMD: MDElliottMD moved page Pharmacopedia:Pharmacogenomics sandbox/Enzyme CYP2C19 to Enzyme:CYP2C19: Migrate enzyme entity pages from Pharmacogenomics sandbox to the new Enzyme: namespace