Enzyme:CYP3A4 - Revision history

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

2026-05-22T16:53:09Z

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 CYP3A4 substrate table (click to expand)		\|+ style="white-space:nowrap; text-align:left;" \| near-complete CYP3A4 substrate table (click to expand)
	! Substrate !! Therapeutic class !! CYP3A4 contribution !! Clinical notes		! scope="col" \| Substrate !! scope="col" \| Therapeutic class !! scope="col" \| CYP3A4 contribution !! scope="col" \| Clinical notes
	\|-		\|-
	\| [[Alfentanil]] \|\| Opioid analgesic (anesthesia) \|\| major \|\| A classic CYP3A4 probe substrate; major substrate of CYP3A4 inhibitor interactions in the operating room.		\| [[Alfentanil]] \|\| Opioid analgesic (anesthesia) \|\| major \|\| A classic CYP3A4 probe substrate; major substrate of CYP3A4 inhibitor interactions in the operating room.

MDElliottMD: MDElliottMD moved page Pharmacopedia:Pharmacogenomics sandbox/Enzyme CYP3A4 to Enzyme:CYP3A4: Migrate enzyme entity pages from Pharmacogenomics sandbox to the new Enzyme: namespace

2026-05-22T02:55:07Z

MDElliottMD moved page Pharmacopedia:Pharmacogenomics sandbox/Enzyme CYP3A4 to Enzyme:CYP3A4: 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: Revise CYP3A4 Phenotype categories section per parser-claude 2026-05-20: the earlier text flatly stated CYP3A4 has no metabolizer-phenotype classification. That is true for CPIC but not for DPWG, which tiers CYP3A4 into PM/IM/NM on the CYP3A4*22 allele. New text states the CPIC/DPWG disagreement, links the three Phenotype:CYP3A4 pages, and keeps the point that environmental induction/inhibition dominate CYP3A4 variability. Cites DPWG guideline PharmGKB PA166265421. See-also gains the three ph...

2026-05-20T18:55:34Z

Revise CYP3A4 Phenotype categories section per parser-claude 2026-05-20: the earlier text flatly stated CYP3A4 has no metabolizer-phenotype classification. That is true for CPIC but not for DPWG, which tiers CYP3A4 into PM/IM/NM on the CYP3A4*22 allele. New text states the CPIC/DPWG disagreement, links the three Phenotype:CYP3A4 pages, and keeps the point that environmental induction/inhibition dominate CYP3A4 variability. Cites DPWG guideline PharmGKB PA166265421. See-also gains the three ph...

← Older revision		Revision as of 18:55, 20 May 2026
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	== Phenotype categories ==		== Phenotype categories ==
	~~Unlike~~ [[Enzyme:CYP2D6\|CYP2D6]] ~~and several of~~ the CYP2C enzymes, ~~CYP3A4~~ does not ~~have~~ a ~~well~~-~~defined poor-metabolizer / intermediate / normal / ultrarapid~~ phenotype classification ~~useful at~~ the ~~bedside. Population~~ variability in CYP3A4 activity is wide (roughly 10- to 30-fold between individuals) ~~but~~ is dominated by environmental and physiological factors rather than by frankly inactivating star-allele genetics. The ~~clinically actionable polymorphisms~~ that ~~do exist are subtler~~ than the ~~corresponding stories at~~ CYP2D6 or CYP2C19.		CYP3A4 phenotyping is a more contested matter than the phenotyping of [[Enzyme:CYP2D6\|CYP2D6]] or the CYP2C enzymes, and the two major pharmacogenomics consortia do not agree on it. The Clinical Pharmacogenetics Implementation Consortium (CPIC) does not assign CYP3A4 a metabolizer-phenotype classification; in CPIC's framing the population variability in CYP3A4 activity, though wide (roughly 10- to 30-fold between individuals), is dominated by environmental and physiological factors rather than by frankly inactivating star-allele genetics. The Dutch Pharmacogenetics Working Group (DPWG) takes the other position and does define a CYP3A4 phenotype, built around the decreased-function ''CYP3A4\22'' allele: a poor metabolizer carries two ''\22'' alleles, an intermediate metabolizer one, and a normal metabolizer none. The DPWG framework underlies that group's guidance on, for example, quetiapine dosing.<ref name="dpwg-cyp3a4">Dutch Pharmacogenetics Working Group (DPWG). Gene-drug interaction guideline for CYP3A4 (PharmGKB guideline annotation PA166265421). Royal Dutch Pharmacists Association (KNMP). Available via https://www.pharmgkb.org/.</ref> The wiki indexes the DPWG phenotype categories at [[Phenotype:CYP3A4 poor metabolizer]], [[Phenotype:CYP3A4 intermediate metabolizer]], and [[Phenotype:CYP3A4 normal metabolizer]]. Even under the DPWG framework, the CYP3A4 phenotype is a less settled construct than the CYP2D6 or CYP2C19 phenotypes, and environmental induction and inhibition remain the dominant sources of CYP3A4 variability whatever a patient's ''\*22'' genotype.

	== Major variants ==		== Major variants ==
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	* [[Enzyme:CYP3A5]], the related isoform with the more clinically actionable polymorphism		* [[Enzyme:CYP3A5]], the related isoform with the more clinically actionable polymorphism
	* [[Enzyme:CYP2D6]], [[Enzyme:CYP2C19]], [[Enzyme:CYP2C9]], [[Enzyme:CYP1A2]], [[Enzyme:CYP2B6]]		* [[Enzyme:CYP2D6]], [[Enzyme:CYP2C19]], [[Enzyme:CYP2C9]], [[Enzyme:CYP1A2]], [[Enzyme:CYP2B6]]
			* [[Phenotype:CYP3A4 poor metabolizer]], [[Phenotype:CYP3A4 intermediate metabolizer]], [[Phenotype:CYP3A4 normal metabolizer]] (the DPWG CYP3A4 metabolizer phenotypes)
	* [[Tacrolimus]], [[Simvastatin]], [[Midazolam]], [[Cyclosporine]] (canonical CYP3A4 substrate examples)		* [[Tacrolimus]], [[Simvastatin]], [[Midazolam]], [[Cyclosporine]] (canonical CYP3A4 substrate examples)
	* [[Rifampin]], [[Clarithromycin]], grapefruit juice (canonical inducer and inhibitor examples)		* [[Rifampin]], [[Clarithromycin]], grapefruit juice (canonical inducer and inhibitor examples)

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...

2026-05-19T22:39:07Z

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...

Show changes

MDElliottMD: Pharmacogenomics entity page: CYP3A4. Second of 10 canonical enzyme pages in Phase 1 (after CYP2D6 yesterday). Sandboxed under Pharmacopedia:Pharmacogenomics sandbox/ until interface-claude registers the Enzyme: namespace; will move to Enzyme:CYP3A4 thereafter. Covers tissue distribution (gut + liver), substrate spectrum (~50% of all medicines), inhibitor strength/kinetic-class taxonomy (grapefruit mechanism-based story), inducer pharmacology (rifampin PXR/CAR), CYP3A5*3 cross-reference, summ...

2026-05-19T16:32:18Z

Pharmacogenomics entity page: CYP3A4. Second of 10 canonical enzyme pages in Phase 1 (after CYP2D6 yesterday). Sandboxed under Pharmacopedia:Pharmacogenomics sandbox/ until interface-claude registers the Enzyme: namespace; will move to Enzyme:CYP3A4 thereafter. Covers tissue distribution (gut + liver), substrate spectrum (~50% of all medicines), inhibitor strength/kinetic-class taxonomy (grapefruit mechanism-based story), inducer pharmacology (rifampin PXR/CAR), CYP3A5*3 cross-reference, summ...

New page

'''CYP3A4''' (cytochrome P450 3A4) is the single most clinically consequential drug-metabolizing enzyme in the human body. It is encoded by the ''CYP3A4'' gene on chromosome 7q22.1 and is expressed at high levels in both the liver and the wall of the small intestine. Approximately half of all medicines now in clinical use are substrates of CYP3A4 to a meaningful degree, a figure unmatched by any other cytochrome P450, and the enzyme's promiscuity, its strong inducibility, and its susceptibility to both reversible and mechanism-based inhibition make it the central player in a disproportionate share of drug-drug interactions.<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>

== Tissue distribution ==
CYP3A4 sits at two places along the path a swallowed medicine takes into the body, and both matter clinically. In the small-intestinal wall, CYP3A4 is by far the dominant cytochrome, accounting for roughly 80% of total intestinal CYP protein,<ref name="paine2006">Paine MF, Hart HL, Ludington SS, Haining RL, Rettie AE, Zeldin DC. The human intestinal cytochrome P450 "pie". ''Drug Metabolism and Disposition''. 2006 May;34(5):880-886. PMID: 16467132.</ref> and it metabolizes its substrates during their first pass through the enterocytes before they ever reach the portal circulation. In the liver, CYP3A4 accounts for roughly 30 to 40% of total hepatic CYP protein, again the largest share of any single isoform, and it continues the work of clearance that the gut wall began. For a high-extraction substrate like felodipine or simvastatin, the intestinal contribution dominates first-pass metabolism; for a low-extraction substrate like midazolam given orally, both compartments contribute, while for the same drug given intravenously, only the hepatic compartment is in play. This is why grapefruit juice affects oral midazolam strongly but intravenous midazolam barely at all, a fact that has practical consequences for any clinician trying to anticipate an interaction.

== Function and substrate spectrum ==
CYP3A4 catalyzes oxidation, hydroxylation, N- and O-dealkylation, and a number of less common reactions across an unusually wide chemical-structural space. Its active site is large, flexible, and capable of binding more than one substrate molecule simultaneously, which is the molecular basis for its catholic substrate range. Medicines metabolized substantially by CYP3A4 include, in no particular order: many of the [[:Category:Benzodiazepines|benzodiazepines]] ([[Midazolam|midazolam]], [[Alprazolam|alprazolam]], [[Triazolam|triazolam]]); the calcium channel blockers ([[Amlodipine|amlodipine]], [[Felodipine|felodipine]], [[Verapamil|verapamil]], [[Diltiazem|diltiazem]]); several of the statins ([[Simvastatin|simvastatin]], [[Atorvastatin|atorvastatin]], [[Lovastatin|lovastatin]]); the immunosuppressants [[Cyclosporine|cyclosporine]] and [[Tacrolimus|tacrolimus]]; many anti-cancer agents (including [[Vincristine|vincristine]], [[Paclitaxel|paclitaxel]], [[Imatinib|imatinib]], [[Ibrutinib|ibrutinib]]); the macrolide antibiotics [[Erythromycin|erythromycin]] and [[Clarithromycin|clarithromycin]] (which are simultaneously substrates and inhibitors); the HIV protease inhibitors; the direct oral anticoagulants [[Apixaban|apixaban]] and [[Rivaroxaban|rivaroxaban]]; the opioid [[Fentanyl|fentanyl]] and the synthetic opioid [[Methadone|methadone]]; the antifungals [[Itraconazole|itraconazole]] and [[Ketoconazole|ketoconazole]] (likewise substrates and inhibitors); endogenous steroids including cortisol, testosterone, and many of the estrogens; and a long list of others.<ref name="wilkinson2005" /> When a medicine's clearance route is not immediately obvious, CYP3A4 is the right first guess.

== Phenotype categories ==
Unlike [[Enzyme:CYP2D6|CYP2D6]] and several of the CYP2C enzymes, CYP3A4 does not have a well-defined poor-metabolizer / intermediate / normal / ultrarapid phenotype classification useful at the bedside. Population variability in CYP3A4 activity is wide (roughly 10- to 30-fold between individuals) but is dominated by environmental and physiological factors rather than by frankly inactivating star-allele genetics. The clinically actionable polymorphisms that do exist are subtler than the corresponding stories at CYP2D6 or CYP2C19.

== Major variants ==
* '''*1''', reference, fully functional
* '''*22''' (rs35599367), a decreased-function allele associated with reduced CYP3A4 expression. Carriers tend to need lower doses of CYP3A4 substrates such as [[Tacrolimus|tacrolimus]], some statins, and [[Quetiapine|quetiapine]]. Clinically relevant but not yet a routine pre-prescription test in most settings.
* Many other rare variants (*2 through more than *30) have been catalogued at PharmVar but most have not been linked to robust clinical effects.

The closely related gene ''CYP3A5'' sits next to ''CYP3A4'' on the same chromosomal locus and produces an enzyme with overlapping but not identical substrate preferences. The '''CYP3A5\*3''' variant is much more clinically consequential than any CYP3A4 polymorphism: most people of European ancestry carry two copies and produce essentially no functional CYP3A5, while many people of African ancestry retain a functional copy. CYP3A5 expressers clear [[Tacrolimus|tacrolimus]] markedly faster than non-expressers, which has become a routine pre-transplant pharmacogenomic consideration. See [[Enzyme:CYP3A5]] for the CYP3A5 story in full; this page is CYP3A4.

== Inhibitors ==
CYP3A4 inhibition produces some of the most clinically dangerous drug-drug interactions in medicine because of the breadth of the substrate list. Inhibitors are classified by both strength and kinetic class.

'''Strong reversible-competitive inhibitors''':
* [[Ketoconazole|Ketoconazole]] (the experimental probe; rarely co-prescribed clinically because of its own hepatotoxicity)
* [[Itraconazole|Itraconazole]]
* Voriconazole, posaconazole, isavuconazole
* [[Cobicistat|Cobicistat]] (used deliberately as a pharmacokinetic "booster" of HIV antivirals)
* HIV protease inhibitors as a class

'''Strong mechanism-based inhibitors''':
* '''Furanocoumarins in grapefruit juice''' (chiefly bergamottin and 6',7'-dihydroxybergamottin), which covalently inactivate intestinal CYP3A4. The interaction was identified serendipitously by Bailey and colleagues in 1991, who noticed that grapefruit juice given to mask the taste of ethanol in a felodipine pharmacokinetic study produced an unexpectedly large rise in plasma felodipine concentrations.<ref name="bailey1991">Bailey DG, Spence JD, Munoz C, Arnold JMO. Interaction of citrus juices with felodipine and nifedipine. ''Lancet''. 1991 Feb 2;337(8736):268-269. PMID: 1671113.</ref> Because the inhibition is covalent, the affected enzyme does not recover on the timescale of grapefruit-juice elimination; activity returns over the de-novo synthesis half-life of intestinal CYP3A4, roughly 24 to 72 hours. The clinical consequence is that timing the dose to avoid the juice (for example, taking a statin at night and drinking the juice in the morning) does not abolish the interaction.
* [[Clarithromycin|Clarithromycin]] and [[Erythromycin|erythromycin]] (mechanism-based component; azithromycin does NOT cause this interaction)
* [[Ritonavir|Ritonavir]] at therapeutic exposure (mechanism-based component is part of why it boosts so effectively)

'''Moderate inhibitors''':
* [[Diltiazem|Diltiazem]], [[Verapamil|verapamil]] (calcium channel blockers that are simultaneously substrates of their target enzyme)
* [[Fluconazole|Fluconazole]]
* [[Aprepitant|Aprepitant]]
* [[Cimetidine|Cimetidine]]

== Inducers ==
CYP3A4 is among the most strongly inducible enzymes in human pharmacology. Induction is mediated principally by the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), which up-regulate transcription of the ''CYP3A4'' gene in response to a wide range of xenobiotic signals.

The clinical archetype is '''[[Rifampin|rifampin]]''', which over a roughly two-week induction window can increase CYP3A4 activity to two or three times baseline, with corresponding reductions of 50 to 90% in plasma exposures of CYP3A4 substrates. Other meaningful inducers include [[Carbamazepine|carbamazepine]], [[Phenytoin|phenytoin]], [[Phenobarbital|phenobarbital]], the antiretroviral [[Efavirenz|efavirenz]], and the herbal product St John's Wort.<ref name="niemi2003">Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivistö KT. Pharmacokinetic interactions with rifampicin: clinical relevance. ''Clinical Pharmacokinetics''. 2003;42(9):819-850. PMID: 12882588.</ref> Induction is slow on the way in (days to weeks to plateau) and slow on the way out (days to weeks to decay after the inducer is stopped), and so the period after discontinuing an inducer is a particularly hazardous window in which substrate concentrations can rise rapidly toward toxicity.

== Clinical implications, summary ==
For any medicine that depends materially on CYP3A4 for clearance:

* '''Strong CYP3A4 inhibitor co-prescribed''': anticipate substantial, sometimes dramatic, rises in substrate plasma concentrations. For high-extraction substrates given orally, the rise can be five-fold or more. Either avoid the combination or reduce the substrate dose with monitoring. Note the kinetic-class distinction: reversible inhibition resolves with the inhibitor's elimination, but mechanism-based inhibition (grapefruit, clarithromycin, ritonavir) persists for days after the inhibitor is stopped.
* '''Strong CYP3A4 inducer co-prescribed''': anticipate substantial loss of substrate effect. For medicines with a narrow therapeutic window or essential clinical role (oral contraceptives, transplant immunosuppressants, antiretrovirals), induction often forces a regimen change rather than a dose adjustment.
* '''Inducer recently stopped''': the most dangerous window. Reintroduce substrates only with monitoring; expect concentrations to rise over the next 1 to 3 weeks as CYP3A4 expression returns to baseline.
* '''Genotype-based pre-prescription dosing''' is not a routine practice for CYP3A4 itself, in contrast to [[Enzyme:CYP2D6|CYP2D6]] (for codeine and tramadol) and [[Enzyme:CYP2C19|CYP2C19]] (for clopidogrel). The closest practical exception is ''CYP3A5'' genotyping before [[Tacrolimus|tacrolimus]] dosing in solid-organ transplantation.

== See also ==
* [[Enzyme:CYP3A5]], the related isoform with the more clinically actionable polymorphism
* [[Enzyme:CYP2D6]], [[Enzyme:CYP2C19]], [[Enzyme:CYP2C9]], [[Enzyme:CYP1A2]], [[Enzyme:CYP2B6]]
* [[Tacrolimus]], [[Simvastatin]], [[Midazolam]], [[Cyclosporine]] (canonical CYP3A4 substrate examples)
* [[Rifampin]], [[Clarithromycin]], grapefruit juice (canonical inducer and inhibitor examples)
* [[:Category:Drug-metabolizing enzymes]] (when this category is built out)

== References ==

<references/>

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