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Enzyme:CYP3A4: Difference between revisions

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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...
 
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 ==
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.
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.<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> When a medicine's clearance route is not immediately obvious, CYP3A4 is the right first guess.
 
The table below collects the clinically important CYP3A4 substrates by therapeutic class, with each entry tagged by the contribution CYP3A4 makes to overall clearance: '''major''' (CYP3A4 is the predominant route; reversible and mechanism-based interactions are clinically expected), '''moderate''' (CYP3A4 contributes meaningfully but other routes carry comparable load), '''minor''' (CYP3A4 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.
 
{| 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)
! Substrate !! Therapeutic class !! CYP3A4 contribution !! Clinical notes
|-
| [[Alfentanil]] || Opioid analgesic (anesthesia) || major || A classic CYP3A4 probe substrate; major substrate of CYP3A4 inhibitor interactions in the operating room.
|-
| [[Alprazolam]] || Benzodiazepine || major || Oversedation risk with CYP3A4 inhibitors; reduced effect with inducers.
|-
| [[Amiodarone]] || Antiarrhythmic || partial || Mixed CYP3A4 + CYP2C8; amiodarone is itself a moderate CYP3A4 inhibitor (long-tail interaction via desethylamiodarone).
|-
| [[Amlodipine]] || Calcium channel blocker (dihydropyridine) || major || Hypotension with strong CYP3A4 inhibitors.
|-
| [[Apixaban]] || Direct oral anticoagulant (Xa) || major || Mixed CYP3A4 + P-gp; FDA labeling cautions against use with strong dual CYP3A4 / P-gp inhibitors or inducers.
|-
| [[Aripiprazole]] || Atypical antipsychotic || partial || Mixed CYP3A4 + CYP2D6; both routes matter.
|-
| [[Atorvastatin]] || Statin (HMG-CoA reductase inhibitor) || major || Rhabdomyolysis risk with strong CYP3A4 inhibitors; dose caps apply when co-prescribed with cyclosporine, certain HIV antiretrovirals, etc.
|-
| [[Bortezomib]] || Proteasome inhibitor (anti-cancer) || moderate || Mixed CYP3A4 + CYP2C19.
|-
| [[Buprenorphine]] || Opioid partial agonist || major || Increased exposures with CYP3A4 inhibitors.
|-
| [[Buspirone]] || Anxiolytic (5-HT1A partial agonist) || major || Up to 13-fold AUC increase with strong CYP3A4 inhibitors; one of the largest single-medicine CYP3A4-interaction signals in the literature.
|-
| [[Carbamazepine]] || Antiepileptic, mood stabilizer || major || Substrate AND strong inducer (auto-induces its own metabolism over the first weeks of therapy).
|-
| [[Cisapride]] || Prokinetic (withdrawn) || major || Withdrawn from most markets in 2000 because of fatal CYP3A4-inhibitor-driven torsades de pointes (the case-defining example of why CYP3A4 interactions matter).
|-
| [[Clarithromycin]] || Macrolide antibiotic || major || Substrate AND mechanism-based inhibitor; one of the most clinically dangerous CYP3A4 inhibitors in everyday practice.
|-
| [[Colchicine]] || Anti-inflammatory (gout, FMF) || major || Mixed CYP3A4 + P-gp; severe and sometimes fatal toxicity with strong CYP3A4 inhibitors, especially clarithromycin.
|-
| [[Cyclophosphamide]] || Antineoplastic (alkylating) || partial || Mixed CYP3A4 + CYP2B6 (dominant); CYP3A4 contributes to bioactivation.
|-
| '''[[Cyclosporine]]''' || Calcineurin inhibitor (immunosuppression) || major || '''Narrow therapeutic window.''' Strong CYP3A4 inhibitor co-prescription routinely produces toxic concentrations; strong induction produces graft loss. Therapeutic drug monitoring is standard.
|-
| [[Darifenacin]] || Antimuscarinic (overactive bladder) || major || Dose cap with strong CYP3A4 inhibitors.
|-
| [[Diltiazem]] || Calcium channel blocker (non-dihydropyridine) || major || Substrate AND moderate inhibitor of CYP3A4.
|-
| [[Donepezil]] || Cholinesterase inhibitor (dementia) || partial || Mixed CYP3A4 + CYP2D6.
|-
| [[Dronedarone]] || Antiarrhythmic || major || Substrate AND moderate CYP3A4 inhibitor.
|-
| [[Erythromycin]] || Macrolide antibiotic || major || Substrate AND mechanism-based inhibitor; the original "macrolide interaction" archetype.
|-
| [[Estradiol]] || Endogenous estrogen / hormone therapy || major || CYP3A4 is one of several oxidative routes; strong inducers reduce oral contraceptive efficacy.
|-
| [[Everolimus]] || mTOR inhibitor (immunosuppression, oncology) || major || Narrow therapeutic window like cyclosporine; therapeutic drug monitoring standard.
|-
| [[Felodipine]] || Calcium channel blocker (dihydropyridine) || major || The substrate that revealed the grapefruit-juice interaction (Bailey 1991).
|-
| '''[[Fentanyl]]''' || Opioid analgesic || major || Respiratory-depression risk with strong CYP3A4 inhibitors (clarithromycin, fluconazole, ritonavir).
|-
| [[Finasteride]] || 5-alpha reductase inhibitor (BPH, hair loss) || major || Inducers reduce exposure substantially.
|-
| [[Ibrutinib]] || BTK inhibitor (oncology) || major || FDA labeling caps dose with strong CYP3A4 inhibitors; avoid with strong inducers.
|-
| [[Imatinib]] || Tyrosine kinase inhibitor (oncology) || major || Substrate AND moderate CYP3A4 inhibitor; mixed pharmacology.
|-
| [[Indinavir]] || HIV protease inhibitor || major || Substrate AND moderate inhibitor; nephrolithiasis risk linked to high exposures.
|-
| [[Itraconazole]] || Triazole antifungal || major || Substrate AND strong CYP3A4 inhibitor; one of the strongest used in clinical interaction studies as a probe inhibitor.
|-
| [[Ivabradine]] || HCN-channel blocker (heart rate) || major || Avoid with strong CYP3A4 inhibitors.
|-
| [[Ketoconazole]] || Imidazole antifungal || major || Substrate AND the canonical strong CYP3A4 inhibitor used as the probe in regulatory interaction studies (though clinical use has receded because of hepatotoxicity).
|-
| [[Lopinavir]] || HIV protease inhibitor || major || Substrate AND inhibitor; co-formulated with ritonavir as a deliberate booster.
|-
| [[Lovastatin]] || Statin || major || Rhabdomyolysis risk; among the most CYP3A4-dependent statins (along with simvastatin).
|-
| [[Methadone]] || Opioid (chronic pain, OUD) || major || Mixed CYP3A4 + CYP2B6 + CYP2D6; QT prolongation magnified by elevated exposures.
|-
| '''[[Midazolam]]''' || Benzodiazepine (anesthesia, ICU) || major || '''Canonical CYP3A4 probe substrate.''' Used in interaction studies as the standard read-out for in-vivo CYP3A4 activity. Oral midazolam is heavily affected by intestinal CYP3A4 (and grapefruit); IV midazolam is affected only by hepatic CYP3A4.
|-
| [[Nifedipine]] || Calcium channel blocker (dihydropyridine) || major || Hypotension with strong CYP3A4 inhibitors.
|-
| [[Norethindrone]] || Progestin (oral contraceptive component) || partial || Strong inducers reduce contraceptive efficacy.
|-
| [[Ondansetron]] || 5-HT3 antagonist (antiemetic) || partial || Mixed CYP3A4 + CYP1A2 + CYP2D6.
|-
| [[Oxycodone]] || Opioid analgesic || partial || Mixed CYP3A4 (major route to noroxycodone) + CYP2D6 (minor route to oxymorphone).
|-
| [[Paclitaxel]] || Taxane antineoplastic || major || Mixed CYP3A4 + CYP2C8; both routes matter.
|-
| [[Quetiapine]] || Atypical antipsychotic || major || Substantial AUC increase with strong CYP3A4 inhibitors; oversedation risk.
|-
| [[Quinidine]] || Antiarrhythmic / CYP2D6 probe inhibitor || major || Also a strong CYP2D6 inhibitor at therapeutic exposures.
|-
| [[Repaglinide]] || Meglitinide (oral hypoglycaemic) || partial || Mixed CYP3A4 + CYP2C8.
|-
| [[Rivaroxaban]] || Direct oral anticoagulant (Xa) || major || Mixed CYP3A4 + P-gp; same caution pattern as apixaban.
|-
| [[Sildenafil]] || PDE5 inhibitor || major || Strong CYP3A4 inhibitors (eg ketoconazole, ritonavir) raise sildenafil AUC several-fold; dose caps apply.
|-
| '''[[Simvastatin]]''' || Statin || major || '''Among the most CYP3A4-dependent medicines.''' Strong inhibitors are functionally contraindicated; rhabdomyolysis risk is the limiting toxicity. The simvastatin-erythromycin and simvastatin-clarithromycin interactions are among the most frequently cited in pharmacy literature.
|-
| [[Sirolimus]] || mTOR inhibitor (immunosuppression) || major || Narrow therapeutic window; therapeutic drug monitoring standard.
|-
| [[Sufentanil]] || Opioid analgesic (anesthesia) || major || Same interaction pattern as alfentanil.
|-
| [[Tacrolimus]] || Calcineurin inhibitor (immunosuppression) || major || '''Narrow therapeutic window.''' Heavy CYP3A4 dependence with strong genotype-modulation via CYP3A5 (see Major variants section). Therapeutic drug monitoring standard.
|-
| [[Tadalafil]] || PDE5 inhibitor || major || Same CYP3A4-inhibitor caution pattern as sildenafil.
|-
| [[Tamsulosin]] || Alpha-1 blocker (BPH) || major || Hypotension risk with strong CYP3A4 inhibitors.
|-
| [[Testosterone]] || Endogenous androgen / hormone therapy || major || CYP3A4 is one of several oxidative routes.
|-
| [[Triazolam]] || Benzodiazepine || major || Oversedation risk with strong inhibitors; effectively contraindicated with ritonavir, clarithromycin, ketoconazole.
|-
| [[Vardenafil]] || PDE5 inhibitor || major || Same CYP3A4-inhibitor caution pattern as sildenafil and tadalafil.
|-
| [[Venetoclax]] || BCL-2 inhibitor (oncology) || major || FDA labeling: dose reduction or avoidance with strong CYP3A4 inhibitors during ramp-up because of tumor-lysis-syndrome risk.
|-
| [[Verapamil]] || Calcium channel blocker (non-dihydropyridine) || major || Substrate AND moderate inhibitor of CYP3A4.
|-
| [[Vincristine]] || Vinca alkaloid (oncology) || major || Severe neurotoxicity with strong CYP3A4 inhibitors; particularly dangerous in pediatric ALL regimens with azole antifungal co-prescription.
|}


== Phenotype categories ==
== Phenotype categories ==
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* '''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.
* '''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.
* '''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.
== 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 CYP3A4 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 CYP3A4 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 CYP3A4 (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:CYP3A4"