View source for CYP3A4

{{Short description|Enzyme that metabolizes substances by oxidation}}
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{{Infobox enzyme
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| EC_number = 1.14.14.56
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'''Cytochrome P450 3A4''' (abbreviated '''CYP3A4''') ({{EC number|1.14.13.97}}) is an important [[enzyme]] in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It [[organic redox reaction|oxidizes]] small foreign organic molecules ([[xenobiotic]]s), such as [[toxin]]s or drugs, so that they can be removed from the body. It is highly homologous to  [[CYP3A5]], another important CYP3A enzyme.

While many drugs are deactivated by CYP3A4, there are also some drugs that are ''activated'' by the enzyme. Some substances, such as some drugs and [[furanocoumarin]]s present in [[grapefruit]] juice, interfere with the action of CYP3A4. These substances will, therefore, either amplify or weaken the action of those drugs that are modified by CYP3A4.

CYP3A4 is a member of the [[cytochrome P450]] family of oxidizing enzymes. Several other members of this family are also involved in drug metabolism, but CYP3A4 is the most common and the most versatile one. Like all members of this family, it is a [[hemoprotein]], i.e. a [[protein]] containing a [[heme]] group with an iron atom. In humans, the CYP3A4 protein is encoded by the ''CYP3A4'' [[gene]].<ref name="pmid8269949">{{cite journal | vauthors = Hashimoto H, Toide K, Kitamura R, Fujita M, Tagawa S, Itoh S, Kamataki T | title = Gene structure of CYP3A4, an adult-specific form of cytochrome P450 in human livers, and its transcriptional control | journal = European Journal of Biochemistry | volume = 218 | issue = 2 | pages = 585–95 | date = December 1993 | pmid = 8269949 | doi = 10.1111/j.1432-1033.1993.tb18412.x | doi-access = free }}</ref> This gene is part of a cluster of cytochrome P450 genes on [[chromosome 7 (human)|chromosome 7q22.1]].<ref name="pmid1391968">{{cite journal | vauthors = Inoue K, Inazawa J, Nakagawa H, Shimada T, Yamazaki H, Guengerich FP, Abe T | title = Assignment of the human cytochrome P-450 nifedipine oxidase gene (CYP3A4) to chromosome 7 at band q22.1 by fluorescence in situ hybridization | journal = The Japanese Journal of Human Genetics | volume = 37 | issue = 2 | pages = 133–8 | date = June 1992 | pmid = 1391968 | doi = 10.1007/BF01899734 | doi-access = free }}</ref> Previously another CYP3A gene, ''CYP3A3'', was thought to exist; however, it is now thought that this sequence represents a transcript variant of ''CYP3A4''. Alternatively-spliced transcript variants encoding different isoforms have been identified.<ref name="refseq"/>

== Function ==
CYP3A4 is a member of the [[cytochrome P450]] [[superfamily (molecular biology)|superfamily]] of [[enzyme]]s. The cytochrome P450 proteins are [[monooxygenase]]s that catalyze many reactions involved in [[drug metabolism]] and synthesis of  [[steroid]]s (including [[cholesterol]]), and other [[lipid]]s.<ref name="refseq">{{NCBI RefSeq|title=CYP3A4 cytochrome P450 family 3 subfamily A member 4 [ Homo sapiens (human) ]|url=https://www.ncbi.nlm.nih.gov/gene/1576}}</ref>

The CYP3A4 protein localizes to the [[endoplasmic reticulum]], and its expression is induced by [[glucocorticoid]]s and some pharmacological agents.<ref name="refseq"/> Cytochrome P450 enzymes metabolize approximately 60% of prescribed drugs, with CYP3A4 responsible for about half of this metabolism;<ref>{{cite journal | vauthors = Zanger UM, Schwab M | title = Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation | journal = Pharmacology & Therapeutics | volume = 138 | issue = 1 | pages = 103–41 | date = April 2013 | pmid = 23333322 | doi = 10.1016/j.pharmthera.2012.12.007 | doi-access = free }}</ref> substrates include [[acetaminophen]] (paracetamol), [[codeine]], [[ciclosporin]] (cyclosporin), [[diazepam]], [[erythromycin]], and [[chloroquine]].<ref name="refseq"/> The enzyme also metabolizes some [[steroid]]s and [[carcinogen]]s.<ref name="entrez">{{EntrezGene|1576}}</ref> Most drugs undergo deactivation by CYP3A4, either directly or by facilitated [[excretion]] from the body. Also, many substances are [[bioactivation|bioactivated]] by CYP3A4 to form their active compounds, and many protoxins are [[toxicated]] into their toxic forms ''(see table below for examples)''.

CYP3A4 also possesses [[epoxygenase]] activity in that it metabolizes [[arachidonic acid]] to [[epoxyeicosatrienoic acid]]s (EETs), i.e. (±)-8,9-, (±)-11,12-, and (±)-14,15-epoxyeicosatrienoic acids.<ref>{{cite journal | vauthors = Bishop-Bailey D, Thomson S, Askari A, Faulkner A, Wheeler-Jones C | title = Lipid-metabolizing CYPs in the regulation and dysregulation of metabolism | journal = Annual Review of Nutrition | volume = 34 | pages = 261–79 | pmid = 24819323 | doi = 10.1146/annurev-nutr-071813-105747 | year = 2014 | url = https://rvc-repository.worktribe.com/preview/1659487/kura-et-al-2023-can-mass-drug-administration-of-moxidectin-accelerate-onchocerciasis-elimination-in-africa.pdf | access-date = 2 February 2024 | archive-date = 18 January 2024 | archive-url = https://web.archive.org/web/20240118040330/https://rvc-repository.worktribe.com/preview/1659487/kura-et-al-2023-can-mass-drug-administration-of-moxidectin-accelerate-onchocerciasis-elimination-in-africa.pdf | url-status = live }}</ref> EETs have a wide range of activities including the promotion of certain types of [[cancer]]s (see [[epoxyeicosatetraenoic acid#cancer|epoxyeicosatetraenoic acid]]). CYP3A4 promotes the growth of various types of human cancer cell lines in culture by producing (±)-14,15-epoxyeicosatrienoic acids, which stimulate these cells to grow.<ref>{{cite journal | vauthors = Fleming I | title = The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease | journal = Pharmacological Reviews | volume = 66 | issue = 4 | pages = 1106–40 | date = October 2014 | pmid = 25244930 | doi = 10.1124/pr.113.007781 | doi-access =  }}</ref>  The CYP3A4 enzyme is also reported to have fatty acid monooxgenase activity for metabolizing arachidonic acid to [[20-Hydroxyeicosatetraenoic acid]] (20-HETE).<ref name="pmid11375247">{{cite journal | vauthors = Miyata N, Taniguchi K, Seki T, Ishimoto T, Sato-Watanabe M, Yasuda Y, Doi M, Kametani S, Tomishima Y, Ueki T, Sato M, Kameo K | title = HET0016, a potent and selective inhibitor of 20-HETE synthesizing enzyme | journal = British Journal of Pharmacology | volume = 133 | issue = 3 | pages = 325–9 | date = June 2001 | pmid = 11375247 | pmc = 1572803 | doi = 10.1038/sj.bjp.0704101 }}</ref> 20-HETE has a wide range of activities that include growth stimulation in breast and other types of cancers (see [[12-hydroxyeicosatetraenoic acid#cancer|12-hydroxyeicosatetraenoic acid]]).

== Evolution ==
The ''CYP3A4'' gene exhibits a much more complicated upstream regulatory region in comparison with its [[Homology (biology)#Paralogy|paralogs]].<ref name="Qiu_2010">{{cite journal | vauthors = Qiu H, Mathäs M, Nestler S, Bengel C, Nem D, Gödtel-Armbrust U, Lang T, Taudien S, Burk O, Wojnowski L | s2cid = 205602787 | title = The unique complexity of the CYP3A4 upstream region suggests a nongenetic explanation of its expression variability | journal = Pharmacogenetics and Genomics | volume = 20 | issue = 3 | pages = 167–78 | date = March 2010 | pmid = 20147837 | doi = 10.1097/FPC.0b013e328336bbeb }}</ref> This increased complexity renders the ''CYP3A4'' gene more sensitive to endogenous and exogenous [[pregnane X receptor]] (PXR) and [[constitutive androstane receptor]] (CAR) ligands, instead of relying on gene variants for wider specificity.<ref name="Qiu_2010" /> [[Chimpanzee]] and human CYP3A4 are highly conserved in metabolism of many [[ligands]], although four amino acids positively selected in humans led to a 5-fold [[benzylation]] of [[7-BFC]] in the presence of the [[hepatotoxic]] secondary [[bile acid]] [[lithocholic acid]].<ref name="Kumar_2009">{{cite journal | vauthors = Kumar S, Qiu H, Oezguen N, Herlyn H, Halpert JR, Wojnowski L | title = Ligand diversity of human and chimpanzee CYP3A4: activation of human CYP3A4 by lithocholic acid results from positive selection | journal = Drug Metabolism and Disposition | volume = 37 | issue = 6 | pages = 1328–33 | date = June 2009 | pmid = 19299527 | pmc = 2683693 | doi = 10.1124/dmd.108.024372 }}</ref> This change in consequence contributes to an increased human defense against [[cholestasis]].<ref name="Kumar_2009" />

== Tissue distribution ==
[[Fetus]]es do not express ''CYP3A4'' in their liver tissue, but rather ''[[CYP3A7]]'' ({{EC number|1.14.14.1}}), which acts on a similar range of substrates. CYP3A4 increases to approximately 40% of adult levels in the fourth month of life and 72% at 12 months.<ref name="pmid16928154">{{cite journal | vauthors = Johnson TN, Rostami-Hodjegan A, Tucker GT | s2cid = 25596506 | title = Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children | journal = Clinical Pharmacokinetics | volume = 45 | issue = 9 | pages = 931–56 | year = 2006 | pmid = 16928154 | doi = 10.2165/00003088-200645090-00005 }}</ref><ref name="pmid18043691">{{cite journal | vauthors = Johnson TN, Tucker GT, Rostami-Hodjegan A | title = Development of CYP2D6 and CYP3A4 in the first year of life | journal = Clinical Pharmacology and Therapeutics | volume = 83 | issue = 5 | pages = 670–1 | date = May 2008 | pmid = 18043691 | doi = 10.1038/sj.clpt.6100327 | s2cid = 9714442 }}</ref>

Although CYP3A4 is predominantly found in the liver, it is also present in other organs and tissues of the body, where it may play an important role in metabolism. CP3A4 is the major CYP enzyme in the intestine.<ref name="pmid21142260">{{cite journal | vauthors=Seden K, Dickinson L, Khoo S, David D | title=Grapefruit-drug interactions | journal=[[Drugs (journal)|Drugs]] | volume=70 | issue=18 | pages=2373–2407 | year=2010 |  doi = 10.2165/11585250-000000000-00000 | pmid=21142260 }}</ref> CYP3A4 in the intestine plays an important role in the metabolism of certain drugs. Often this allows [[prodrug]]s to be activated and absorbed, as in the case of the [[histamine antagonist|histamine H<sub>1</sub>-receptor antagonist]] [[terfenadine]].

CYP3A4 has also been identified in the brain, but its role in the [[central nervous system]] is unknown.<ref>{{cite journal | vauthors = Robertson GR, Field J, Goodwin B, Bierach S, Tran M, Lehnert A, Liddle C | s2cid = 17209434 | title = Transgenic mouse models of human CYP3A4 gene regulation | journal = Molecular Pharmacology | volume = 64 | issue = 1 | pages = 42–50 | date = July 2003 | pmid = 12815159 | doi = 10.1124/mol.64.1.42 }}</ref>

== Mechanisms ==
[[Cytochrome P450]] enzymes perform an assortment of modifications on a variety of [[ligand]]s, utilizing its large active site and its ability to bind more than one substrate at a time to perform complicated chemical alterations in the metabolism of endogenous and exogenous compounds. These include [[hydroxylation]], [[epoxide|epoxidation]] of [[olefins]], aromatic [[redox|oxidation]], heteroatom oxidations, N- and O- dealkylation reactions, aldehyde oxidations, [[dehydrogenation]] reactions, and aromatase activity.<ref name="pmid9351897">{{cite journal | vauthors = Schmiedlin-Ren P, Edwards DJ, Fitzsimmons ME, He K, Lown KS, Woster PM, Rahman A, Thummel KE, Fisher JM, Hollenberg PF, Watkins PB | title = Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents. Decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins | journal = Drug Metabolism and Disposition | volume = 25 | issue = 11 | pages = 1228–33 | date = November 1997 | pmid = 9351897 }}</ref><ref name="Shahrokh_2012">{{cite journal | vauthors = Shahrokh K, Cheatham TE, Yost GS | title = Conformational dynamics of CYP3A4 demonstrate the important role of Arg212 coupled with the opening of ingress, egress and solvent channels to dehydrogenation of 4-hydroxy-tamoxifen | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 1820 | issue = 10 | pages = 1605–17 | date = October 2012 | pmid = 22677141 | pmc = 3404218 | doi = 10.1016/j.bbagen.2012.05.011 }}</ref>

Hydroxylation of an [[sp3 bond|sp<sup>3</sup>]] [[C-H bond]] is one of the ways in which CYP3A4 (and cytochrome P450 oxygenases) affects its ligand.<ref name="Meunier_2004">{{cite journal | vauthors = Meunier B, de Visser SP, Shaik S | s2cid = 33927145 | title = Mechanism of oxidation reactions catalyzed by cytochrome p450 enzymes | journal = Chemical Reviews | volume = 104 | issue = 9 | pages = 3947–80 | date = September 2004 | pmid = 15352783 | doi = 10.1021/cr020443g }}</ref> In fact, hydroxylation is sometimes followed by dehydrogenation, leading to more complex metabolites.<ref name="Shahrokh_2012" /> An example of a molecule that undergoes more than one reaction due to CYP3A4 includes [[tamoxifen]], which is hydroxylated to 4-hydroxy-tamoxifen and then dehydrated to 4-hydroxy-tamoxifen quinone methide.<ref name="Shahrokh_2012" />

Two mechanisms have been proposed as the primary pathway of hydroxylation in P450 enzymes. [[File:Hydroxylation Mechanisms of Cytochrome P450 Enzymes.png|thumb|Two of the most commonly proposed mechanisms used for the hydroxylation of an sp<sup>3</sup> C–H bond]] The first pathway suggested is a cage-controlled radical method ("oxygen rebound"), and the second involves a concerted mechanism that does not utilize a radical intermediate but instead acts very quickly via a "[[radical clock]]".<ref name="Meunier_2004" />

== Inhibition through fruit ingestion ==
In 1998, various researchers showed that [[grapefruit]] juice, and grapefruit in general, is a potent inhibitor of CYP3A4, which can affect the metabolism of a variety of drugs, increasing their [[bioavailability]].<ref name="GSE_Drug_Effect">{{cite journal | vauthors = He K, Iyer KR, Hayes RN, Sinz MW, Woolf TF, Hollenberg PF | title = Inactivation of cytochrome P450 3A4 by bergamottin, a component of grapefruit juice | journal = Chemical Research in Toxicology | volume = 11 | issue = 4 | pages = 252–9 | date = April 1998 | pmid = 9548795 | doi = 10.1021/tx970192k }}</ref><ref name="Bailey_DG1998">{{cite journal | vauthors = Bailey DG, Malcolm J, Arnold O, Spence JD | title = Grapefruit juice-drug interactions | journal = British Journal of Clinical Pharmacology | volume = 46 | issue = 2 | pages = 101–10 | date = August 1998 | pmid = 9723817 | pmc = 1873672 | doi = 10.1046/j.1365-2125.1998.00764.x }}</ref><ref name="Carbamazepine">{{cite journal | vauthors = Garg SK, Kumar N, Bhargava VK, Prabhakar SK | title = Effect of grapefruit juice on carbamazepine bioavailability in patients with epilepsy | journal = Clinical Pharmacology and Therapeutics | volume = 64 | issue = 3 | pages = 286–8 | date = September 1998 | pmid = 9757152 | doi = 10.1016/S0009-9236(98)90177-1 | s2cid = 27490726 | doi-access = free }}</ref><ref name="Bailey_DG2004">{{cite journal | vauthors = Bailey DG, Dresser GK | s2cid = 11525439 | title = Interactions between grapefruit juice and cardiovascular drugs | journal = American Journal of Cardiovascular Drugs | volume = 4 | issue = 5 | pages = 281–97 | year = 2004 | pmid = 15449971 | doi = 10.2165/00129784-200404050-00002 }}</ref><ref name="Bressler_R">{{cite journal | vauthors = Bressler R | title = Grapefruit juice and drug interactions. Exploring mechanisms of this interaction and potential toxicity for certain drugs | journal = Geriatrics | volume = 61 | issue = 11 | pages = 12–8 | date = November 2006 | pmid = 17112309 }}</ref> In some cases, this can lead to a fatal interaction with drugs like [[astemizole]] or [[terfenadine]].<ref name="Bailey_DG1998"/> The effect of grapefruit juice with regard to drug absorption was originally discovered in 1989. The first published report on grapefruit drug interactions was in 1991 in the ''Lancet'' entitled "Interactions of Citrus Juices with [[Felodipine]] and [[Nifedipine]]", and was the first reported food-drug interaction clinically. The effects of grapefruit last from 3–7 days, with the greatest effects when juice is taken an hour previous to administration of the drug.<ref name="Clin Pharm">{{cite journal | vauthors = Lilja JJ, Kivistö KT, Neuvonen PJ | title = Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin | journal = Clinical Pharmacology and Therapeutics | volume = 68 | issue = 4 | pages = 384–90 | date = October 2000 | pmid = 11061578 | doi = 10.1067/mcp.2000.110216 | s2cid = 29029956 }}</ref>

In addition to grapefruit, other fruits have similar effects. [[Noni]] (''Morinda citrifolia''), for example, is a [[dietary supplement]] typically consumed as a juice and also inhibits CYP3A4.<ref>{{cite web|url=http://www.mskcc.org/cancer-care/herb/noni|title=Integrative Medicine, Noni|publisher=Memorial Sloan-Kettering Cancer Center|access-date=27 June 2013|archive-date=20 August 2013|archive-url=https://web.archive.org/web/20130820052559/http://www.mskcc.org/cancer-care/herb/noni|url-status=live}}</ref> [[Pomegranate]] juice has shown some inhibition in limited studies, but has not yet demonstrated the effect in humans.<ref>{{cite journal | vauthors = Hidaka M, Okumura M, Fujita K, Ogikubo T, Yamasaki K, Iwakiri T, Setoguchi N, Arimori K | s2cid = 7997718 | title = Effects of pomegranate juice on human cytochrome p450 3A (CYP3A) and carbamazepine pharmacokinetics in rats | journal = Drug Metabolism and Disposition | volume = 33 | issue = 5 | pages = 644–8 | date = May 2005 | pmid = 15673597 | doi = 10.1124/dmd.104.002824 }}</ref><ref name="pmid31924158">{{cite journal |vauthors=Anlamlert W, Sermsappasuk P |title=Pomegranate Juice does not Affect the Bioavailability of Cyclosporine in Healthy Thai Volunteers |journal=Curr Clin Pharmacol |volume=15 |issue=2 |pages=145–151 |date=2020 |pmid=31924158 |pmc=7579232 |doi=10.2174/1574884715666200110153125}}</ref>

== Variability ==
While over 28 [[single nucleotide polymorphism]]s (SNPs) have been identified in the ''CYP3A4'' gene, it has been found that this does not translate into significant interindividual variability {{lang|la|in vivo}}. It can be supposed that this may be due to the induction of CYP3A4 on exposure to substrates.

CYP3A4 alleles that have been reported to have minimal function compared to wild-type include CYP3A4*6 (an A17776 insertion) and CYP3A4*17 (F189S). Both of these SNPs led to decreased catalytic activity with certain ligands, including [[testosterone]] and [[nifedipine]] in comparison to wild-type metabolism.<ref name="pmid16004554">{{cite journal | vauthors = Lee SJ, Goldstein JA | title = Functionally defective or altered CYP3A4 and CYP3A5 single nucleotide polymorphisms and their detection with genotyping tests | journal = Pharmacogenomics | volume = 6 | issue = 4 | pages = 357–71 | date = June 2005 | pmid = 16004554 | doi = 10.1517/14622416.6.4.357 | url = https://zenodo.org/record/1236271 | access-date = 25 May 2020 | archive-date = 29 July 2020 | archive-url = https://web.archive.org/web/20200729005806/https://zenodo.org/record/1236271 | url-status = live }}</ref> By contrast, ''CYP3A4*1G'' allele has more potent enzymatic activity compared to ''CYP3A4*1A'' (the wild-type allele).<ref name="Alkattan A 2021">Alkattan A, Alsalameen E. Polymorphisms of genes related to phase-I metabolic enzymes affecting the clinical efficacy and safety of clopidogrel treatment. Expert Opin Drug Metab Toxicol. 2021 Apr 30. doi: 10.1080/17425255.2021.1925249. Epub ahead of print. PMID 33931001.</ref>

Variability in CYP3A4 function can be determined noninvasively by the [[erythromycin breath test]] (ERMBT). The ERMBT estimates {{Lang|la|in vivo}} CYP3A4 activity by measuring the radiolabelled carbon dioxide exhaled after an intravenous dose of (<sup>14</sup>C-''N''-methyl)-[[erythromycin]].<ref name="pmid7987401">{{cite journal | vauthors = Watkins PB | title = Noninvasive tests of CYP3A enzymes | journal = Pharmacogenetics | volume = 4 | issue = 4 | pages = 171–84 | date = August 1994 | pmid = 7987401 | doi = 10.1097/00008571-199408000-00001 | url = https://cdr.lib.unc.edu/record/uuid:8d5c6276-d350-4216-b108-276f2be1d59d }}</ref>

== Induction ==
CYP3A4 is [[Enzyme induction and inhibition|induced]] by a wide variety of [[Ligand (biochemistry)|ligand]]s. These ligands bind to the [[pregnane X receptor]] (PXR). The activated PXR complex forms a heterodimer with the [[retinoid X receptor]] (RXR), which binds to the [[XREM]] region of the ''CYP3A4'' gene. XREM is a regulatory region of the ''CYP3A4'' gene, and binding causes a cooperative interaction with proximal promoter regions of the gene, resulting in increased transcription and expression of CYP3A4. Activation of the PXR/RXR heterodimer initiates [[Transcription (genetics)|transcription]] of the CYP3A4 promoter region and gene. Ligand binding increases when in the presence of CYP3A4 ligands, such as in the presence of [[aflatoxins|aflatoxin]] B1, M1, and G1. Indeed, due to the enzyme's large and malleable active site, it is possible for the enzyme to bind multiple ligands at once, leading to potentially detrimental side effects.<ref name="pmid21641981">{{cite journal | vauthors = Ratajewski M, Walczak-Drzewiecka A, Sałkowska A, Dastych J | title = Aflatoxins upregulate CYP3A4 mRNA expression in a process that involves the PXR transcription factor | journal = Toxicology Letters | volume = 205 | issue = 2 | pages = 146–53 | date = August 2011 | pmid = 21641981 | doi = 10.1016/j.toxlet.2011.05.1034 }}</ref>

Induction of CYP3A4 has been shown to vary in humans depending on sex. Evidence shows an increased [[clearance (pharmacology)|drug clearance]] by CYP3A4 in women, even when accounting for differences in body weight. A study by Wolbold et al. (2003) found that the median CYP3A4 levels measured from surgically removed liver samples of a random sample of women exceeded CYP3A4 levels in the livers of men by 129%. CYP3A4 [[messenger RNA|mRNA]] transcripts were found in similar proportions, suggesting a pre-translational mechanism for the up-regulation of CYP3A4 in women. The exact cause of this elevated level of enzyme in women is still under speculation, however studies have elucidated other mechanisms (such as CYP3A5 or CYP3A7 compensation for lowered levels of CYP3A4) that affect drug clearance in both men and women.<ref name="pmid14512885">{{cite journal | vauthors = Wolbold R, Klein K, Burk O, Nüssler AK, Neuhaus P, Eichelbaum M, Schwab M, Zanger UM | title = Sex is a major determinant of CYP3A4 expression in human liver | journal = Hepatology | volume = 38 | issue = 4 | pages = 978–88 | date = October 2003 | pmid = 14512885 | doi = 10.1053/jhep.2003.50393 | doi-access =  }}</ref>

CYP3A4 substrate activation varies amongst different animal species. Certain ligands activate human PXR, which promotes CYP3A4 transcription, while showing no activation in other species. For instance, mouse PXR is not activated by [[rifampicin]] and human PXR is not activated by pregnenolone 16α-carbonitrile<ref name="Gonzalez">{{cite journal | vauthors = Gonzalez FJ | title = CYP3A4 and pregnane X receptor humanized mice | journal = Journal of Biochemical and Molecular Toxicology | volume = 21 | issue = 4 | pages = 158–62 | year = 2007 | pmid = 17936928 | doi = 10.1002/jbt.20173 | s2cid = 21501739 | url = https://zenodo.org/record/1229206 | access-date = 6 September 2019 | archive-date = 29 July 2020 | archive-url = https://web.archive.org/web/20200729031129/https://zenodo.org/record/1229206 | url-status = live }}</ref> In order to facilitate study of CYP3A4 functional pathways ''in vivo,'' mouse strains have been developed using [[transgene]]s in order to produce null/human CYP3A4 and PXR crosses. Although humanized hCYP3A4 mice successfully expressed the enzyme in their intestinal tract, low levels of hCYP3A4 were found in the liver.<ref name="Gonzalez" /> This effect has been attributed to CYP3A4 regulation by the [[growth hormone]] signal transduction pathway.<ref name="Gonzalez" /> In addition to providing an ''in vivo'' model, humanized CYP3A4 mice (hCYP3A4) have been used to further emphasize gender differences in CYP3A4 activity.<ref name="Gonzalez" />

CYP3A4 activity levels have also been linked to diet and environmental factors, such as duration of exposure to xenobiotic substances.<ref name="Crago">{{cite journal | vauthors = Crago J, Klaper RD | title = Influence of gender, feeding regimen, and exposure duration on gene expression associated with xenobiotic metabolism in fathead minnows ({{lang|la|Pimephales promelas}}) | journal = Comparative Biochemistry and Physiology. Toxicology & Pharmacology | volume = 154 | issue = 3 | pages = 208–12 | date = September 2011 | pmid = 21664292 | doi = 10.1016/j.cbpc.2011.05.016 }}</ref> Due to the enzyme's extensive presence in the intestinal mucosa, the enzyme has shown sensitivity to starvation symptoms and is upregulated in defense of adverse effects. Indeed, in fatheaded minnows, unfed female fish were shown to have increased PXR and CYP3A4 expression, and displayed a more pronounced response to xenobiotic factors after exposure after several days of starvation.<ref name="Crago" /> By studying animal models and keeping in mind the innate differences in CYP3A4 activation, investigators can better predict drug metabolism and side effects in human CYP3A4 pathways.

==Turnover==
Estimates of the [[protein turnover|turnover]] rate of human CYP3A4 vary widely. For hepatic CYP3A4, ''in vivo'' methods yield estimates of the enzyme [[Biological half-life|half-life]] mainly in the range of 70 to 140 hours, whereas ''in vitro'' methods give estimates from 26 to 79 hours.<ref name = "Yang"/> Turnover of gut CYP3A4 is likely to be a function of the rate of [[enterocyte]] [[cell cycle|renewal]]; an indirect approach based on the recovery of activity following exposure to grapefruit juice yields measurements in the 12- to 33-hour range.<ref name = "Yang">{{cite journal | vauthors = Yang J, Liao M, Shou M, Jamei M, Yeo KR, Tucker GT, Rostami-Hodjegan A | title = Cytochrome p450 turnover: regulation of synthesis and degradation, methods for determining rates, and implications for the prediction of drug interactions | journal = Current Drug Metabolism | volume = 9 | issue = 5 | pages = 384–94 | date = June 2008 | pmid = 18537575 | doi = 10.2174/138920008784746382 }}</ref>

==Technology==
Due to membrane-bound CYP3A4's natural propensity to conglomerate, it has historically been difficult to study drug binding in both solution and on surfaces. Co-crystallization is difficult since the substrates tend to have a low [[Dissociation constant|K<sub>D</sub>]] (between 5–150&nbsp;μM) and low solubility in aqueous solutions.<ref name="Sev">{{cite journal | vauthors = Sevrioukova IF, Poulos TL | title = Structural and mechanistic insights into the interaction of cytochrome P4503A4 with bromoergocryptine, a type I ligand | journal = The Journal of Biological Chemistry | volume = 287 | issue = 5 | pages = 3510–7 | date = January 2012 | pmid = 22157006 | pmc = 3271004 | doi = 10.1074/jbc.M111.317081 | doi-access = free }}</ref> A successful strategy in isolating the bound enzyme is the functional stabilization of monomeric CYP3A4 on silver [[nanoparticle]]s produced from [[nanolithography|nanosphere lithography]] and analyzed via localized [[surface plasmon resonance]] spectroscopy (LSPR).<ref name="Das">{{cite journal | vauthors = Das A, Zhao J, Schatz GC, Sligar SG, Van Duyne RP | title = Screening of type I and II drug binding to human cytochrome P450-3A4 in nanodiscs by localized surface plasmon resonance spectroscopy | journal = Analytical Chemistry | volume = 81 | issue = 10 | pages = 3754–9 | date = May 2009 | pmid = 19364136 | pmc = 4757437 | doi = 10.1021/ac802612z }}</ref> These analyses can be used as a high-sensitivity assay of drug binding, and may become integral in further high-throughput assays utilized in initial drug discovery testing. In addition to LSPR, CYP3A4-Nanodisc complexes have been found helpful in other applications including [[Solid-state nuclear magnetic resonance|solid-state NMR]], redox potentiometry, and [[enzyme kinetics|steady-state enzyme kinetics]].<ref name="Das" />

== Ligands == <!--St. John's wort has link here-->
Following are lists of selected [[enzyme substrate|substrates]], [[enzyme induction and inhibition|inducers]] and [[enzyme induction and inhibition|inhibitors]] of CYP3A4. Where classes of agents are listed, there may be exceptions within the class.

=== Substrates ===
The substrates of CYP3A4 are:
* some [[immunosuppressant]]s:
** [[ciclosporin]] (cyclosporin),<ref name=Flockhart/><ref name=FASS>[[FASS (drug formulary)]]: [http://www.fass.se/LIF/produktfakta/fakta_lakare_artikel.jsp?articleID=18352 Swedish environmental classification of pharmaceuticals] {{Webarchive|url=https://web.archive.org/web/20020611044953/http://www.fass.se/LIF/produktfakta/fakta_lakare_artikel.jsp?articleID=18352 |date=11 June 2002 }} Facts for prescribers (Fakta för förskrivare). Retrieved July 2011</ref>
** [[tacrolimus]],<ref name=Flockhart/><ref name=FASS/>
** [[sirolimus]],<ref name=Flockhart/><ref name=FASS/>
** [[upadacitinib]];<ref name="Rinvoq-2020">"[https://www.ema.europa.eu/en/documents/assessment-report/rinvoq-epar-public-assessment-report_en.pdf Rinvoq: EPAR – Public assessment report] {{Webarchive|url=https://web.archive.org/web/20200721125405/https://www.ema.europa.eu/en/documents/assessment-report/rinvoq-epar-public-assessment-report_en.pdf |date=21 July 2020 }}" (PDF). [[European Medicines Agency]]. 5 March 2020. Archived (PDF) from the original on 21 July 2020. Retrieved 21 July 2020.</ref><ref name="Austria-Codex-DE">''Austria-Codex'' (in German). Vienna: Österreichischer Apothekerverlag. 2020. Rinvoq 15 mg Retardtabletten.</ref>
* many [[chemotherapeutic]]s:
** [[docetaxel]],<ref name=Flockhart/><ref name=FASS/>
** [[tamoxifen]],<ref name=Flockhart/><ref name=FASS/>
** [[paclitaxel]],<ref name=Flockhart/><ref name=FASS/>
** [[cyclophosphamide]],<ref name=FASS/>
** [[doxorubicin]],<ref name=FASS/>
** [[erlotinib]],<ref>{{cite web |title=Erlotinib |url=https://www.drugs.com/ppa/erlotinib.html |quote=Metabolized primarily by CYP3A4 and, to a lesser degree, by CYP1A2 and the extrahepatic isoform CYP1A1 |access-date=10 April 2018 |archive-date=24 December 2019 |archive-url=https://web.archive.org/web/20191224052924/https://www.drugs.com/ppa/erlotinib.html |url-status=live }}</ref>
** [[etoposide]],<ref name=FASS/>
** [[ifosfamide]],<ref name=FASS/>
** [[teniposide]],<ref name=FASS/>
** [[vinblastine]],<ref name=FASS/>
** [[vincristine]],<ref name=Flockhart/>
** [[vindesine]],<ref name=FASS/>
** [[imatinib]],<ref name=Flockhart/>
** [[irinotecan]],<ref name=Flockhart/>
** [[sorafenib]],<ref name=Flockhart/>
** [[sunitinib]],<ref name=Flockhart/>
** [[vemurafenib]],<ref name=Flockhart/>
** [[temsirolimus]],<ref name=Flockhart/>
** [[anastrozole]],
** [[gefitinib]];
* [[azole antifungal]]s:
** [[ketoconazole]]<ref name=FASS/>
** [[itraconazole]]<ref name=FASS/>
* [[macrolide antibiotics|macrolide]]s (except [[azithromycin]]):<ref name="Flockhart" />
** [[clarithromycin]],<ref name="Flockhart" /><ref name="FASS" />
** [[erythromycin]],<ref name="Flockhart" />
** [[telithromycin]];<ref name="Flockhart" />
* [[dapsone]]<ref name=Flockhart/> (in [[leprosy]]),
* [[tricyclic antidepressants]]:
** [[amitriptyline]],<ref name=FASS/>
** [[clomipramine]],<ref name=FASS/>
** [[imipramine]],<ref name=FASS/>
** [[cyclobenzaprine]];<ref>{{cite web|url=http://www.drugbank.ca/drugs/DB00924|title=Cyclobenzaprine|publisher=DrugBank|access-date=10 April 2018|archive-date=27 October 2018|archive-url=https://web.archive.org/web/20181027220500/https://www.drugbank.ca/drugs/DB00924|url-status=live}}</ref>
* [[Selective serotonin reuptake inhibitor|SSRI antidepressants]] :
** [[citalopram]]<ref name=FASS/>
** [[norfluoxetine]]<ref name=FASS/>
** [[sertraline]]<ref name=FASS/>
* some other antidepressants:
** [[mirtazapine]]<ref name=FASS/> ([[noradrenergic and specific serotonergic antidepressant|NaSSA]]),
** [[nefazodone]]<ref name=FASS/> ([[Atypical antidepressant|atypical]]),
** [[reboxetine]]<ref name=FASS/> ([[Norepinephrine reuptake inhibitor|NRI]]),
** [[venlafaxine]]<ref name=FASS/> ([[serotonin-norepinephrine reuptake inhibitor|SNRI]]),
** [[trazodone]]<ref name=Flockhart/> ([[serotonin antagonist and reuptake inhibitor|SARI]]),
** [[vilazodone]]<ref name=FASS/> ([[Serotonin modulator and stimulator|serotonin modulator]]),
* [[buspirone]]<ref name=Flockhart/><ref name=FASS/> ([[anxiolytic]]),
* [[antipsychotics]]:
** [[haloperidol]],<ref name=Flockhart/><ref name=FASS/>
** [[aripiprazole]],<ref name=Flockhart/>
** [[risperidone]],<ref name=Flockhart/>
** [[ziprasidone]],<ref name=Flockhart/>
** [[pimozide]],<ref name=FASS/>
** [[quetiapine]],<ref name=Flockhart/>
** [[lurasidone]];<ref>{{cite book |vauthors=Azhar Y, Shaban K |chapter=Lurasidone |date=2022 |chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK541057/ |title=StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=31082101 |access-date=14 October 2022 |archive-date=18 May 2023 |archive-url=https://web.archive.org/web/20230518045845/https://www.ncbi.nlm.nih.gov/books/NBK541057/ |url-status=live }}</ref>
* [[opioids]] (mainly analgesics):
** [[alfentanil]],<ref name=Flockhart/><ref name=FASS/>
** [[buprenorphine]]<ref name="pmid19773542">{{cite journal | vauthors = Moody DE, Fang WB, Lin SN, Weyant DM, Strom SC, Omiecinski CJ | title = Effect of rifampin and nelfinavir on the metabolism of methadone and buprenorphine in primary cultures of human hepatocytes | journal = Drug Metabolism and Disposition | volume = 37 | issue = 12 | pages = 2323–9 | date = December 2009 | pmid = 19773542 | pmc = 2784702 | doi = 10.1124/dmd.109.028605 }}</ref> ([[analgesic]], [[Opioid use disorder#Management|addiction maintenance treatment]]),
** [[codeine]]<ref name=Flockhart/> ([[analgesic]], [[antitussive]], [[antidiarrheal]]),
** [[fentanyl]],<ref name=Flockhart/>
** [[hydrocodone]]<ref>{{cite journal|journal=British Journal of Clinical Pharmacology|title=CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes|vauthors=Hutchinson MR, Menelaou A, Foster DJ, Coller JK, Somogyi AA |pmid=14998425|volume=57|issue=3|date=Mar 2004|pages=287–97|doi=10.1046/j.1365-2125.2003.02002.x|pmc=1884456}}</ref> (partial involvement, not the bioactivation factor),
** [[methadone]]<ref name=Flockhart/> ([[analgesic]], [[Opioid use disorder#Management|addiction maintenance treatment]]),
** [[levacetylmethadol]],<ref name=Flockhart/>
** [[tramadol]] ([[analgesic]], [[Disease#Refractory disease|refractory]] [[restless legs syndrome#Medications 2|RLS treatment]]);
* [[benzodiazepines]]:
** [[alprazolam]],<ref name=Flockhart/><ref name=FASS/>
** [[midazolam]],<ref name=Flockhart/><ref name=FASS/>
** [[triazolam]],<ref name=Flockhart/><ref name=FASS/>
** [[diazepam]],<ref name=Flockhart/> (bioactivation to [[desmethyldiazepam]])
** [[clonazepam]];<ref>{{cite journal | vauthors = Tanaka E | title = Clinically significant pharmacokinetic drug interactions with benzodiazepines | journal = Journal of Clinical Pharmacy and Therapeutics | volume = 24 | issue = 5 | pages = 347–355 | date = October 1999 | pmid = 10583697 | doi = 10.1046/j.1365-2710.1999.00247.x | s2cid = 22229823 | doi-access = free }}</ref>
* some [[hypnotic]]s:
** [[zopiclone]],<ref name=FASS/>
** [[zaleplon]],<ref name=Flockhart/>
** [[zolpidem]],<ref name=Flockhart/>
* [[donepezil]]<ref name=FASS/> ([[acetylcholinesterase inhibitor]]),
* [[statin]]s (except [[pravastatin]]<ref name="Flockhart" /> and [[rosuvastatin]]<ref name="Flockhart" />):
** [[atorvastatin]],<ref name="Flockhart" /><ref name="FASS" />
** [[lovastatin]],<ref name="Flockhart" /><ref name="FASS" />
** [[simvastatin]],<ref name="FASS" />
** [[cerivastatin]];<ref name="Flockhart" />
* [[calcium channel blockers]]:
** [[diltiazem]]<ref name=Flockhart/><ref name=FASS/> ([[sensitive substrate]]<ref name="Sutton_1997">{{cite journal | vauthors = Sutton D, Butler AM, Nadin L, Murray M | title = Role of CYP3A4 in human hepatic diltiazem N-demethylation: inhibition of CYP3A4 activity by oxidized diltiazem metabolites | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 282 | issue = 1 | pages = 294–300 | date = July 1997 | pmid = 9223567 }}</ref>),
** [[felodipine]]<ref name=Flockhart/><ref name=FASS/> (sensitive substrate<ref name="U S Food and Drug Administration Home Page 2009">{{cite web | title=Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers | website=U S Food and Drug Administration Home Page | date=25 June 2009 | url=https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm#table2-2 | access-date=1 February 2019 | archive-date=23 April 2019 | archive-url=https://web.archive.org/web/20190423033345/https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#table2-2 | url-status=dead }}</ref><ref name="Lown Bailey Fontana Janardan pp. 2545–2553">{{cite journal | vauthors = Lown KS, Bailey DG, Fontana RJ, Janardan SK, Adair CH, Fortlage LA, Brown MB, Guo W, Watkins PB | title = Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression | journal = The Journal of Clinical Investigation | volume = 99 | issue = 10 | pages = 2545–53 | date = May 1997 | pmid = 9153299 | pmc = 508096 | doi = 10.1172/jci119439 | publisher = American Society for Clinical Investigation }}</ref><ref name="Bailey Bend Arnold Tran 1996 pp. 25–33">{{cite journal | vauthors = Bailey DG, Bend JR, Arnold JM, Tran LT, Spence JD | title = Erythromycin-felodipine interaction: magnitude, mechanism, and comparison with grapefruit juice | journal = Clinical Pharmacology and Therapeutics | volume = 60 | issue = 1 | pages = 25–33 | date = July 1996 | pmid = 8689808 | doi = 10.1016/s0009-9236(96)90163-0 | publisher = Springer Nature | s2cid = 1246705 }}</ref><ref name="Guengerich Brian Iwasaki Sari 1991 pp. 1838–44">{{cite journal | vauthors = Guengerich FP, Brian WR, Iwasaki M, Sari MA, Bäärnhielm C, Berntsson P | title = Oxidation of dihydropyridine calcium channel blockers and analogues by human liver cytochrome P-450 IIIA4 | journal = Journal of Medicinal Chemistry | volume = 34 | issue = 6 | pages = 1838–44 | date = June 1991 | pmid = 2061924 | doi=10.1021/jm00110a012}}</ref>),
** [[nifedipine]]<ref name=Flockhart/><ref name=FASS/> (sensitive substrate<ref name="Katoh Nakajima Yamazaki Yokoi 2001 pp. 505–13">{{cite journal | vauthors = Katoh M, Nakajima M, Yamazaki H, Yokoi T | title = Inhibitory effects of CYP3A4 substrates and their metabolites on P-glycoprotein-mediated transport | journal = European Journal of Pharmaceutical Sciences | volume = 12 | issue = 4 | pages = 505–13 | date = February 2001 | pmid = 11231118 | doi=10.1016/s0928-0987(00)00215-3}}</ref><ref name="Foti Rock Wienkers Wahlstrom 2010 pp. 981–987">{{cite journal | vauthors = Foti RS, Rock DA, Wienkers LC, Wahlstrom JL | s2cid = 6823063 | title = Selection of alternative CYP3A4 probe substrates for clinical drug interaction studies using in vitro data and in vivo simulation | journal = Drug Metabolism and Disposition | volume = 38 | issue = 6 | pages = 981–7 | date = June 2010 | pmid = 20203109 | doi = 10.1124/dmd.110.032094 | publisher = American Society for Pharmacology & Experimental Therapeutics (ASPET) }}</ref><ref>{{cite journal | vauthors = Odou P, Ferrari N, Barthélémy C, Brique S, Lhermitte M, Vincent A, Libersa C, Robert H | title = Grapefruit juice-nifedipine interaction: possible involvement of several mechanisms | journal = Journal of Clinical Pharmacy and Therapeutics | volume = 30 | issue = 2 | pages = 153–8 | date = April 2005 | pmid = 15811168 | doi = 10.1111/j.1365-2710.2004.00618.x | s2cid = 30463290 | doi-access = free }}</ref><ref name="DailyMed Nifedipine extended release 2012">{{cite web | title=NIFEDIPINE EXTENDED RELEASE- nifedipine tablet, extended release | website=DailyMed | date=29 November 2012 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4617417a-08df-4417-a944-dfc30de183db | access-date=1 February 2019 | quote=Drug Interactions: Nifedipine is mainly eliminated by metabolism and is a substrate of CYP3A. Inhibitors and inducers of CYP3A can impact the exposure to nifedipine and, consequently, its desirable and undesirable effects. In vitro and in vivo data indicate that nifedipine can inhibit the metabolism of drugs that are substrates of CYP3A, thereby increasing the exposure to other drugs. Nifedipine is a vasodilator, and coadministration of other drugs affecting blood pressure may result in pharmacodynamic interactions. | archive-date=31 January 2022 | archive-url=https://web.archive.org/web/20220131061535/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4617417a-08df-4417-a944-dfc30de183db | url-status=live }}</ref>),
** [[verapamil]]<ref name=Flockhart/><ref name=FASS/> (sensitive substrate<ref name="Zhang Guo Lin Benet 1998 pp. 360–6">{{cite journal | vauthors = Zhang Y, Guo X, Lin ET, Benet LZ | title = Overlapping substrate specificities of cytochrome P450 3A and P-glycoprotein for a novel cysteine protease inhibitor | journal = Drug Metabolism and Disposition | volume = 26 | issue = 4 | pages = 360–6 | date = April 1998 | pmid = 9531525 }}</ref><ref name="Stringer Mallet Clarke Lindenfeld 1992 pp. 35–8">{{cite journal | vauthors = Stringer KA, Mallet J, Clarke M, Lindenfeld JA | title = The effect of three different oral doses of verapamil on the disposition of theophylline | journal = European Journal of Clinical Pharmacology | volume = 43 | issue = 1 | pages = 35–8 | year = 1992 | pmid = 1505606 | doi=10.1007/bf02280751| s2cid = 8942097 }}</ref><ref name="Nielsen-Kudsk Buhl Johannessen 1990 pp. 101–3">{{cite journal | vauthors = Nielsen-Kudsk JE, Buhl JS, Johannessen AC | title = Verapamil-induced inhibition of theophylline elimination in healthy humans | journal = Pharmacology & Toxicology | volume = 66 | issue = 2 | pages = 101–3 | date = February 1990 | pmid = 2315261 | doi=10.1111/j.1600-0773.1990.tb00713.x}}</ref><ref name="Gin Stringer Welage Wilton 1989 pp. 728–32">{{cite journal | vauthors = Gin AS, Stringer KA, Welage LS, Wilton JH, Matthews GE | title = The effect of verapamil on the pharmacokinetic disposition of theophylline in cigarette smokers | journal = Journal of Clinical Pharmacology | volume = 29 | issue = 8 | pages = 728–32 | date = August 1989 | pmid = 2778093 | doi=10.1002/j.1552-4604.1989.tb03407.x| s2cid = 20446675 }}</ref><ref name="Sirmans Pieper Lalonde Smith 1988 pp. 29–34">{{cite journal | vauthors = Sirmans SM, Pieper JA, Lalonde RL, Smith DG, Self TH | title = Effect of calcium channel blockers on theophylline disposition | journal = Clinical Pharmacology and Therapeutics | volume = 44 | issue = 1 | pages = 29–34 | date = July 1988 | pmid = 3391002 | doi=10.1038/clpt.1988.108| s2cid = 39570845 }}</ref><ref name="Robson Miners Birkett 1988 pp. 397–400">{{cite journal | vauthors = Robson RA, Miners JO, Birkett DJ | title = Selective inhibitory effects of nifedipine and verapamil on oxidative metabolism: effects on theophylline | journal = British Journal of Clinical Pharmacology | volume = 25 | issue = 3 | pages = 397–400 | date = March 1988 | pmid = 3358901 | pmc = 1386365 | doi=10.1111/j.1365-2125.1988.tb03319.x}}</ref><ref name="Abernethy Egan Dickinson Carrum 1988 pp. 994–9">{{cite journal | vauthors = Abernethy DR, Egan JM, Dickinson TH, Carrum G | title = Substrate-selective inhibition by verapamil and diltiazem: differential disposition of antipyrine and theophylline in humans | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 244 | issue = 3 | pages = 994–9 | date = March 1988 | pmid = 3252045 }}</ref>),
** [[amlodipine]]<ref name=Flockhart/> (sensitive substrate<ref name="Katoh_2000">{{cite journal | vauthors = Katoh M, Nakajima M, Yamazaki H, Yokoi T | title = Inhibitory potencies of 1,4-dihydropyridine calcium antagonists to P-glycoprotein-mediated transport: comparison with the effects on CYP3A4 | journal = Pharmaceutical Research | volume = 17 | issue = 10 | pages = 1189–97 | date = October 2000 | pmid = 11145223 | doi = 10.1023/a:1007568811691 | s2cid = 24304693 }}</ref>),
** [[lercanidipine]],<ref name=Flockhart/>
** [[nitrendipine]],<ref name=Flockhart/>
** [[nisoldipine]],<ref name=Flockhart/>
* [[amiodarone]]<ref name=FASS/> ([[class III antiarrhythmic]]),
* [[dronedarone]]<ref name=FASS/> ([[class III antiarrhythmic]]),
* [[quinidine]]<ref name=Flockhart/> ([[class I antiarrhythmic agent|class I antiarrhythmic]]),
* [[PDE5 inhibitor]]s:
** [[sildenafil]],<ref name=Flockhart/><ref name=FASS/>
** [[tadalafil]],<ref>{{cite web | title = Active ingredient: Tadalafil - Brands, Medical Use, Clinical Data | url = http://www.druglib.com/activeingredient/tadalafil/ | publisher = Druglib.com | access-date = 13 March 2022 | archive-date = 28 November 2022 | archive-url = https://web.archive.org/web/20221128145825/http://www.druglib.com/activeingredient/tadalafil/ | url-status = live }}</ref>
* [[kinin]]s<ref name=FASS/> ([[vasodilator]]s, [[smooth muscle]] contractors),
* [[steroid]]s:
** [[sex hormones]] (agonists and antagonists):
*** [[finasteride]]<ref name=Flockhart/><ref name=FASS/> ([[antiandrogen]]),
*** [[estradiol]]<ref name=Flockhart/> ([[estrogen]]),
*** [[progesterone]],<ref name=Flockhart/>
*** [[ethinylestradiol]]<ref name=FASS/> ([[hormonal contraceptive]]),
*** [[testosterone]]<ref name=Flockhart/> ([[androgen]]),
*** [[toremifene]]<ref name=FASS/> ([[selective estrogen receptor modulator|SERM]]),
*** [[bicalutamide]];<ref name=AZ>{{cite journal | vauthors = Cockshott ID | title = Bicalutamide: clinical pharmacokinetics and metabolism | journal = Clinical Pharmacokinetics | volume = 43 | issue = 13 | pages = 855–78 | year = 2004 | pmid = 15509184 | doi = 10.2165/00003088-200443130-00003 | s2cid = 29912565 }}</ref>
** [[glucocorticoid]]s:
*** [[budesonide]],<ref name=FASS/>
*** [[hydrocortisone]] ([[cortisol]]),<ref name=Flockhart/><ref name="pmid34633961">{{cite journal | vauthors = Aquinos BM, García Arabehety J, Canteros TM, de Miguel V, Scibona P, Fainstein-Day P | title = [Adrenal crisis associated with modafinil use] | language = es | journal = Medicina | volume = 81 | issue = 5 | pages = 846–849 | year = 2021 | pmid = 34633961 }}</ref>
*** [[dexamethasone]],<ref name=Flockhart/>
*** [[fluticasone]];<ref>{{cite journal | vauthors = Ledger T, Tong W, Rimmer J | title = Iatrogenic Cushing's syndrome with inhaled fluticasone | journal = Australian Prescriber | volume = 42 | issue = 4 | pages = 139–140 | date = August 2019 | pmid = 31427846 | pmc = 6698236 | doi = 10.18773/austprescr.2019.040 }}</ref>
* some [[H1-receptor antagonist|H<sub>1</sub>-receptor antagonists]] (H<sub>1</sub> [[antihistamine]]s):
** [[ketotifen]],<ref name="El-Kommos-2015">{{cite journal | doi=10.1016/j.ancr.2014.11.003 | title=Analysis for commonly prescribed non-sedating antihistamines | date=2015 | journal=Analytical Chemistry Research | volume=3 | pages=1–12 | vauthors = El-Kommos ME, El-Gizawy SM, Atia NN, Hosny NM | doi-access=free }}</ref><ref name="pmid17357376">{{cite journal |vauthors=Jáuregui I, Mullol J, Bartra J, del Cuvillo A, Dávila I, Montoro J, Sastre J, Valero AL |title=H1 antihistamines: psychomotor performance and driving |journal=J Investig Allergol Clin Immunol |volume=16 |issue= Suppl 1|pages=37–44 |date=2006 |pmid=17357376}}</ref><ref name="pmid35538735">{{cite journal |vauthors=Li L, Liu R, Peng C, Chen X, Li J |title=Pharmacogenomics for the efficacy and side effects of antihistamines |journal=Exp Dermatol |volume=31 |issue=7 |pages=993–1004 |date=July 2022 |pmid=35538735 |doi=10.1111/exd.14602}}</ref><ref name="pmid11764306">{{cite journal |vauthors=Merk HF |title=Standard treatment: the role of antihistamines |journal=J Investig Dermatol Symp Proc |volume=6 |issue=2 |pages=153–6 |date=November 2001 |pmid=11764306 |doi=10.1046/j.0022-202x.2001.00032.x|doi-access=free | title-link=doi }}</ref>
** [[terfenadine]],<ref name="Flockhart" /><ref name="FASS" />
** [[astemizole]],<ref name="Flockhart" /><ref name="pmid11259984">{{cite journal | vauthors = Matsumoto S, Yamazoe Y | title = Involvement of multiple human cytochromes P450 in the liver microsomal metabolism of astemizole and a comparison with terfenadine | journal = British Journal of Clinical Pharmacology | volume = 51 | issue = 2 | pages = 133–42 | date = February 2001 | pmid = 11259984 | pmc = 2014443 | doi = 10.1111/j.1365-2125.2001.01292.x }}</ref>
** [[chlorphenamine]];<ref name="Flockhart" />
* [[protease inhibitors]]:
** [[indinavir]],<ref name=Flockhart/><ref name=FASS/>
** [[ritonavir]],<ref name=Flockhart/><ref name=FASS/>
** [[saquinavir]],<ref name=Flockhart/><ref name=FASS/>
** [[nelfinavir]];<ref name=Flockhart/><ref name=FASS/>
* non-nucleoside [[reverse-transcriptase inhibitors]] ([[antiretroviral drugs]]):
** [[nevirapine]]<ref name=FASS/><ref name="Marzinke-2016">{{cite book |vauthors=Marzinke MA |title=Chapter 6 - Therapeutic Drug Monitoring of Antiretrovirals |chapter=Therapeutic Drug Monitoring of Antiretrovirals |date=2016-01-01 |series=Clinical Challenges in Therapeutic Drug Monitoring |pages=135–163 |veditors=Clarke W, Dasgupta A |chapter-url=https://www.sciencedirect.com/science/article/pii/B9780128020258000064 |access-date=2024-02-06 |place=San Diego |publisher=Elsevier |doi=10.1016/B978-0-12-802025-8.00006-4 |isbn=978-0-12-802025-8 |archive-date=2 May 2024 |archive-url=https://web.archive.org/web/20240502101129/https://www.sciencedirect.com/science/article/abs/pii/B9780128020258000064 |url-status=live }}</ref>
** [[delavirdine]],<ref name="Marzinke-2016"/>
** [[efavirenz]],<ref name="Marzinke-2016"/>
** [[etravirine]],<ref name="Marzinke-2016"/>
** [[rilpivirine]];<ref name="Marzinke-2016"/>
* [[albendazole]]<ref>Enzyme [http://www.genome.jp/dbget-bin/www_bget?enzyme+1.14.13.32 1.14.13.32] {{Webarchive|url=https://web.archive.org/web/20170327070920/http://www.genome.jp/dbget-bin/www_bget?enzyme+1.14.13.32 |date=27 March 2017 }} at [[KEGG]]</ref><ref>{{cite web | title=Showing Protein Cytochrome P450 3A4 (HMDBP01018) | series=Human Metabolome Database | access-date=5 August 2017 | url=http://www.hmdb.ca/proteins/HMDBP01018 | archive-date=2 May 2024 | archive-url=https://web.archive.org/web/20240502101115/https://hmdb.ca/proteins/HMDBP01018 | url-status=live }}</ref> ([[antihelminthic]])
* [[cisapride]],<ref name=Flockhart/><ref name=FASS/> ([[5-HT4 receptor]] [[agonist]])
* [[aprepitant]],<ref name=Flockhart/> ([[antiemetic]])
* [[caffeine]],<ref name=Flockhart/> ([[stimulant]])
* [[cocaine]],<ref name=Flockhart/> ([[stimulant]])
* [[cilostazol]],<ref name=Flockhart/> ([[phosphodiesterase inhibitor]])
* [[dextromethorphan]],<ref name=Flockhart/> ([[antitussive]])
* [[domperidone]],<ref name=Flockhart/> ([[antidopaminergic]])
* [[eplerenone]],<ref name=Flockhart/> ([[aldosterone antagonist]])
* [[lidocaine]],<ref name=Flockhart/> ([[local anesthetic]], [[antiarrhythmic]])
* [[ondansetron]],<ref name=Flockhart/>  ([[5-HT3 antagonist]])
* [[propranolol]],<ref name=Flockhart/> ([[beta blocker]])
* [[salmeterol]],<ref name=Flockhart/> ([[beta agonist]])
* [[warfarin]],<ref name="pmid12724615">{{cite journal | vauthors = Daly AK, King BP | title = Pharmacogenetics of oral anticoagulants | journal = Pharmacogenetics | volume = 13 | issue = 5 | pages = 247–52 | date = May 2003 | pmid = 12724615 | doi =  10.1097/00008571-200305000-00002}}</ref> ([[anticoagulant]])
* [[clopidogrel]] becoming [[bioactivated]]<ref name="pmid12515739">{{cite journal | vauthors = Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS, Tait AR, Carville DG, Guyer KE, Bates ER | title = Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction | journal = Circulation | volume = 107 | issue = 1 | pages = 32–7 | date = January 2003 | pmid = 12515739 | doi = 10.1161/01.CIR.0000047060.60595.CC | doi-access = free }}</ref> ([[antiplatelet agent|antiplatelet]]),
* [[2-oxo-clopidogrel]],<ref name="Alkattan A 2021"/>
* [[omeprazole]],<ref name=FASS/> ([[proton pump inhibitor]])
* [[nateglinide]],<ref name=Flockhart/> ([[antidiabetic]])
* [[methoxetamine]],<ref name="pmid23774830">{{cite journal | vauthors = Meyer MR, Bach M, Welter J, Bovens M, Turcant A, Maurer HH | s2cid = 27966043 | title = Ketamine-derived designer drug methoxetamine: metabolism including isoenzyme kinetics and toxicological detectability using GC-MS and LC-(HR-)MSn | journal = Analytical and Bioanalytical Chemistry | volume = 405 | issue = 19 | pages = 6307–21 | date = July 2013 | pmid = 23774830 | doi = 10.1007/s00216-013-7051-6 }}</ref>
* [[montelukast]] ([[leukotriene receptor antagonist]]),
* [[vilaprisan]] ([[selective progesterone receptor modulator]]),
* certain [[angiotensin II receptor blocker]]s:
** [[losartan]] ([[sensitive substrates]])<ref name="LOSARTAN 2018">{{cite web | title=LOSARTAN- losartan potassium tablet, film coated | website=DailyMed | date=26 December 2018 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a98a821c-7b81-4f9b-9801-1a16d71871ce | access-date=6 February 2019 | archive-date=7 February 2019 | archive-url=https://web.archive.org/web/20190207015904/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a98a821c-7b81-4f9b-9801-1a16d71871ce | url-status=live }}</ref><ref name="pmid10877007">{{cite journal |vauthors=Taavitsainen P, Kiukaanniemi K, Pelkonen O |title=In vitro inhibition screening of human hepatic P450 enzymes by five angiotensin-II receptor antagonists |journal=Eur J Clin Pharmacol |volume=56 |issue=2 |pages=135–40 |date=May 2000 |pmid=10877007 |doi=10.1007/s002280050731 |s2cid=26865251 |url=}}</ref>
** [[irbesartan]].<ref name="pmid10877007"/>

=== Inhibitors ===
Inhibitors of CYP3A4 are classified by [[potency (pharmacology)|potency]]:
* a '''Strong inhibitor''' causes at least a 5-fold increase in the plasma [[area under the curve (pharmacokinetics)|AUC values]], or more than 80% decrease in [[clearance (medicine)|clearance]].<ref name=Flockhart/>
* a '''Moderate inhibitor''' causes at least a 2-fold increase in the plasma AUC values, or 50–80% decrease in clearance.<ref name=Flockhart/>
* a '''Weak inhibitor''' causes at least a 1.25-fold but less than 2-fold increase in the plasma AUC values, or 20–50% decrease in clearance.<ref name=Flockhart>{{cite web |vauthors=Flockhart DA |title=Drug Interactions: Cytochrome P<sub>450</sub> Drug Interaction Table |publisher=[[Indiana University School of Medicine]] |year=2007 |url=http://medicine.iupui.edu/flockhart/table.htm |access-date=25 December 2008 |archive-date=10 October 2007 |archive-url=https://web.archive.org/web/20071010053126/http://medicine.iupui.edu/flockhart/table.htm |url-status=live }} Retrieved on 25 December 2008.</ref>

The inhibitors of CYP3A4 are the following substances.

====Strong inhibitors====
* [[boceprevir]],<ref name="FDA_drug_development">{{cite journal|title=Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers|journal=FDA|date=6 May 2023|url=https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers|publisher=US Food and Drug Administration|access-date=21 June 2020|archive-date=4 November 2020|archive-url=https://web.archive.org/web/20201104173036/https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers|url-status=dead}}</ref>
* [[Pharmacologic protease inhibitor|protease inhibitors]]:
** [[ritonavir]],<ref name="Flockhart" /><ref name="FASS" /><ref name="lange6th" />
** [[indinavir]],<ref name="Flockhart" />
** [[nelfinavir]],<ref name="Flockhart" />
** [[saquinavir]];<ref name="Flockhart" />
* some [[Macrolide|macrolide antibiotic]]s:<ref name="lange6th" />
** [[clarithromycin]],<ref name="FDA_drug_development" /><ref name="pmid34467456">{{cite journal |vauthors=Kapetas AJ, Abuhelwa AY, Sorich MJ, McKinnon RA, Rodrigues AD, Rowland A, Hopkins AM |title=Evidence-Based Guidelines for Drug Interaction Studies: Model-Informed Time Course of Intestinal and Hepatic CYP3A4 Inhibition by Clarithromycin |journal=AAPS J |volume=23 |issue=5 |pages=104 |date=August 2021 |pmid=34467456 |doi=10.1208/s12248-021-00632-7 |s2cid=237373341 |url=}}</ref><ref name="pmid12152002">{{cite journal |vauthors=Ushiama H, Echizen H, Nachi S, Ohnishi A |title=Dose-dependent inhibition of CYP3A activity by clarithromycin during Helicobacter pylori eradication therapy assessed by changes in plasma lansoprazole levels and partial cortisol clearance to 6beta-hydroxycortisol |journal=Clin Pharmacol Ther |volume=72 |issue=1 |pages=33–43 |date=July 2002 |pmid=12152002 |doi=10.1067/mcp.2002.125559 |url=|doi-access=free }}</ref><ref name="Flockhart" /><ref name="FASS" /><ref name="pmid37874128">{{cite journal |vauthors=Herdegen T, Cascorbi I |title=Drug Interactions of Tetrahydrocannabinol and Cannabidiol in Cannabinoid Drugs: Recommendations for Clinical Practice |journal=Dtsch Ärztebl Int |volume= 120|issue=49 |pages= 833–840|date=December 2023 |pmid=37874128 |doi=10.3238/arztebl.m2023.0223 |pmc=10824494 |s2cid=264438050 |url=}}</ref><ref name="pmid31628882" />
** [[erythromycin]]<ref name="pmid31628882">{{cite journal |vauthors=Hougaard Christensen MM, Bruun Haastrup M, Øhlenschlaeger T, Esbech P, Arnspang Pedersen S, Bach Dunvald AC, Bjerregaard Stage T, Pilsgaard Henriksen D, Thestrup Pedersen AJ |title=Interaction potential between clarithromycin and individual statins-A systematic review |journal=Basic Clin Pharmacol Toxicol |volume=126 |issue=4 |pages=307–317 |date=April 2020 |pmid=31628882 |doi=10.1111/bcpt.13343 |quote=Erythromycin 500 mg three-four times daily for 6-7 days markedly increased lovastatin exposure (≈6-fold increase in AUC) |url=https://findresearcher.sdu.dk/ws/files/158846448/Interaction_Potential_between_Clarithromycin_and_Individual_Statins_a_Systematic_Review.pdf |access-date=2 February 2024 |archive-date=2 February 2024 |archive-url=https://web.archive.org/web/20240202140200/https://findresearcher.sdu.dk/ws/files/158846448/Interaction_Potential_between_Clarithromycin_and_Individual_Statins_a_Systematic_Review.pdf |url-status=live }}</ref> (although FDA lists it as a moderate inhibitor, and inhibitor of P-glycoprotein, defined as those increasing the AUC of digoxin to ≥1.25-fold);<ref name="FDA_drug_development"/>
** [[telithromycin]]
* [[ceritinib]]
* [[mibefradil]] (used for the treatment of [[hypertension]] and chronic [[angina pectoris]])
* [[nefazodone]] ([[antidepressant]])
* [[ribociclib]]
* [[tucatinib]]
* [[chloramphenicol]] ([[antibiotic]])<ref>{{cite journal | vauthors = Park JY, Kim KA, Kim SL | title = Chloramphenicol is a potent inhibitor of cytochrome P450 isoforms CYP2C19 and CYP3A4 in human liver microsomes | journal = Antimicrobial Agents and Chemotherapy | volume = 47 | issue = 11 | pages = 3464–9 | date = November 2003 | pmid = 14576103 | pmc = 253795 | doi = 10.1128/AAC.47.11.3464-3469.2003 }}</ref>
* some [[azole antifungal]]s:
** [[ketoconazole]],<ref name="Flockhart" /><ref name="FASS" />
** [[itraconazole]],<ref name="FDA_drug_development" /><ref name="Flockhart" /><ref name="FASS" />
** [[posaconazole]],<ref name="FDA-labeling">{{cite web|url=https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm|title=Drug Interactions & Labeling - Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers|author=Center for Drug Evaluation and Research|website=www.fda.gov|access-date=6 August 2018|archive-date=23 April 2019|archive-url=https://web.archive.org/web/20190423033345/https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm|url-status=dead}}</ref>
** [[voriconazole]];<ref name="FDA-labeling" />
* [[cobicistat]],<ref name="FDA-labeling" />
* green tea extract,<ref name="pmid33198812" /><ref name="pmid15499196" /><ref name="pmid19353999" />
* grape seed extract,<ref name="pmid33198812">{{cite journal | vauthors = Darweesh RS, El-Elimat T, Zayed A, Khamis TN, Babaresh WM, Arafat T, Al Sharie AH | title = The effect of grape seed and green tea extracts on the pharmacokinetics of imatinib and its main metabolite, N-desmethyl imatinib, in rats | journal = BMC Pharmacology & Toxicology | volume = 21 | issue = 1 | pages = 77 | date = November 2020 | pmid = 33198812 | pmc = 7670682 | doi = 10.1186/s40360-020-00456-9 | doi-access = free }}</ref><ref name="pmid15499196">{{cite journal | vauthors = Nishikawa M, Ariyoshi N, Kotani A, Ishii I, Nakamura H, Nakasa H, Ida M, Nakamura H, Kimura N, Kimura M, Hasegawa A, Kusu F, Ohmori S, Nakazawa K, Kitada M | display-authors = 6 | title = Effects of continuous ingestion of green tea or grape seed extracts on the pharmacokinetics of midazolam | journal = Drug Metabolism and Pharmacokinetics | volume = 19 | issue = 4 | pages = 280–289 | date = August 2004 | pmid = 15499196 | doi = 10.2133/dmpk.19.280 }}</ref><ref name="pmid19353999">{{cite journal | vauthors = Wanwimolruk S, Wong K, Wanwimolruk P | title = Variable inhibitory effect of different brands of commercial herbal supplements on human cytochrome P-450 CYP3A4 | journal = Drug Metabolism and Drug Interactions | volume = 24 | issue = 1 | pages = 17–35 | date = 2009 | pmid = 19353999 | doi = 10.1515/dmdi.2009.24.1.17 | url = http://pubmed.ncbi.nlm.nih.gov/19353999/ | access-date = 14 October 2023 | url-status = live | s2cid = 27192663 | archive-url = https://web.archive.org/web/20231021225447/https://pubmed.ncbi.nlm.nih.gov/19353999/ | archive-date = 21 October 2023 }}</ref>
* [[dillapiole]] (compound present in [[dill]] plants),<ref>{{cite journal | vauthors = Francis Carballo-Arce A, Raina V, Liu S, Liu R, Jackiewicz V, Carranza D, Arnason JT, Durst T | display-authors = 6 | title = Potent CYP3A4 Inhibitors Derived from Dillapiol and Sesamol | journal = ACS Omega | volume = 4 | issue = 6 | pages = 10915–10920 | date = June 2019 | pmid = 31460189 | pmc = 6648837 | doi = 10.1021/acsomega.9b00897 }}</ref><ref>{{cite journal | vauthors = Briguglio M, Hrelia S, Malaguti M, Serpe L, Canaparo R, Dell'Osso B, Galentino R, De Michele S, Dina CZ, Porta M, Banfi G | display-authors = 6 | title = Food Bioactive Compounds and Their Interference in Drug Pharmacokinetic/Pharmacodynamic Profiles | journal = Pharmaceutics | volume = 10 | issue = 4 | page = 277 | date = December 2018 | pmid = 30558213 | pmc = 6321138 | doi = 10.3390/pharmaceutics10040277 | doi-access = free }}</ref>
* [[apigenin]] (compound present in plants such as [[celery]], [[parsley]], and [[chamomile]])<ref>{{cite journal | vauthors = Kondža M, Bojić M, Tomić I, Maleš Ž, Rezić V, Ćavar I | title = Characterization of the CYP3A4 Enzyme Inhibition Potential of Selected Flavonoids | journal = Molecules | volume = 26 | issue = 10 | page = 3018 | date = May 2021 | pmid = 34069400 | pmc = 8158701 | doi = 10.3390/molecules26103018 | doi-access = free }}</ref>
* ''[[Artemisia annua]]''<ref>{{cite journal | vauthors = Kondža M, Mandić M, Ivančić I, Vladimir-Knežević S, Brizić I | title = ''Artemisia annua'' L. Extracts Irreversibly Inhibit the Activity of CYP2B6 and CYP3A4 Enzymes | journal = Biomedicines | volume = 11 | issue = 1 | pages = 232 | date = January 2023 | pmid = 36672740 | pmc = 9855681 | doi = 10.3390/biomedicines11010232 | doi-access = free }}</ref>

====Moderate inhibitors====
* [[amiodarone]] ([[class III antiarrhythmic]]),<ref name="FDA-labeling" />
* [[aprepitant]],<ref name="FDA_drug_development" /> ([[antiemetic]])
* [[ciprofloxacin]],<ref name="FDA_drug_development" />
* [[conivaptan]],<ref name="FDA_drug_development" />
* [[crizotinib]],<ref name="FDA_drug_development" />
* [[rutin]] ''(in vitro)''<ref name="PMID27749250">{{cite journal | vauthors = Karakurt S | title = Modulatory effects of rutin on the expression of cytochrome P450s and antioxidant enzymes in human hepatoma cells | journal = Acta Pharmaceutica | volume = 66 | issue = 4 | pages = 491–502 | date = December 2016 | pmid = 27749250 | doi = 10.1515/acph-2016-0046 | s2cid = 20274417 | doi-access = free | url = https://hrcak.srce.hr/file/243341 | access-date = 2 February 2024 | archive-date = 18 June 2022 | archive-url = https://web.archive.org/web/20220618102746/https://hrcak.srce.hr/file/243341 | url-status = live }}</ref><ref name="PMID28539725">{{cite journal | vauthors = Ashour ML, Youssef FS, Gad HA, Wink M | title = Inhibition of Cytochrome P450 (CYP3A4) Activity by Extracts from 57 Plants Used in Traditional Chinese Medicine (TCM) | journal = Pharmacognosy Magazine | volume = 13 | issue = 50 | pages = 300–308 | year = 2017 | pmid = 28539725 | pmc = 5421430 | doi = 10.4103/0973-1296.204561 | doi-access = free }}</ref> (dietary [[flavonoid]]),
* [[tofisopam]],<ref name="FDA_drug_development" />
* some [[calcium channel blocker]]s:
** [[verapamil]],<ref name="FDA_drug_development" /><ref name="Flockhart" /><ref name="FDA-labeling" />
** [[diltiazem]];<ref name="Flockhart" />
* some [[azole antifungal]]s:<ref name="lange6th" />
** [[fluconazole]],<ref name="Flockhart" />
** [[miconazole]];<ref>Product Information: ORAVIG(R) buccal tablets, miconazole buccal tablets. Praelia Pharmaceuticals, Inc (per FDA), Cary, NC, 2013.</ref>
* [[bergamottin]]<ref name="pmid34570813">{{cite journal |vauthors=Vetrichelvan O, Gorjala P, Goodman O, Mitra R |title=Bergamottin a CYP3A inhibitor found in grapefruit juice inhibits prostate cancer cell growth by downregulating androgen receptor signaling and promoting G0/G1 cell cycle block and apoptosis |journal=PLOS ONE |volume=16 |issue=9 |pages=e0257984 |date=2021 |pmid=34570813 |pmc=8476002 |doi=10.1371/journal.pone.0257984 |bibcode=2021PLoSO..1657984V |url=|doi-access=free }}</ref><ref name="Flockhart" /> (constituent of [[grapefruit]] juice),
* [[Ciclosporin|cyclosporine]],<ref name="FDA-labeling" />
* [[Dronedarone|donedarone]],<ref name="FDA-labeling" />
* [[fluvoxamine]],<ref name="FDA-labeling" />
* [[imatinib]],<ref name="FDA-labeling" />
* [[Valerian (herb)|valerian]].<ref>{{cite web|url=http://www.rxlist.com/valerian-page3/supplements.htm#Interactions|title=Valerian: Health Benefits, Side Effects, Uses, Dose & Precautions|access-date=10 April 2018|archive-date=16 January 2018|archive-url=https://web.archive.org/web/20180116055514/https://www.rxlist.com/valerian-page3/supplements.htm#Interactions|url-status=dead}}</ref>

====Weak inhibitors====
* [[berberine]]<ref name="pmid34269665">{{cite journal |vauthors=Feng PF, Zhu LX, Jie J, Yang PX, Chen X |title=The Intracellular Mechanism of Berberine-Induced Inhibition of CYP3A4 Activity |journal=Curr Pharm Des |volume=27 |issue=40 |pages=4179–4185 |date=2021 |pmid=34269665 |doi=10.2174/1381612827666210715155809 |s2cid=235960940 |url=}}</ref><ref name="pmid37541764">{{cite journal |vauthors=Nguyen JT, Tian DD, Tanna RS, Arian CM, Calamia JC, Rettie AE, Thummel KE, Paine MF |title=An Integrative Approach to Elucidate Mechanisms Underlying the Pharmacokinetic Goldenseal-Midazolam Interaction: Application of In Vitro Assays and Physiologically Based Pharmacokinetic Models to Understand Clinical Observations |journal=J Pharmacol Exp Ther |volume=387 |issue=3 |pages=252–264 |date=December 2023 |pmid=37541764 |pmc=10658920 |doi=10.1124/jpet.123.001681 |url=}}</ref><ref name="pmid22855269">{{cite journal | vauthors = Hermann R, von Richter O | title = Clinical evidence of herbal drugs as perpetrators of pharmacokinetic drug interactions | journal = Planta Medica | volume = 78 | issue = 13 | pages = 1458–77 | date = September 2012 | pmid = 22855269 | doi = 10.1055/s-0032-1315117 | url = | doi-access = free }}</ref><ref name="pmid30086269">{{cite journal | vauthors = Feng P, Zhao L, Guo F, Zhang B, Fang L, Zhan G, Xu X, Fang Q, Liang Z, Li B | title = The enhancement of cardiotoxicity that results from inhibiton of CYP 3A4 activity and hERG channel by berberine in combination with statins | journal = Chemico-Biological Interactions | volume = 293 | issue = | pages = 115–123 | date = September 2018 | pmid = 30086269 | doi = 10.1016/j.cbi.2018.07.022 | bibcode = 2018CBI...293..115F | s2cid = 206489481 }}</ref> (an [[alkaloid]] found in plants such as [[berberis]] or [[goldenseal]]),
* [[buprenorphine]] ([[analgesic]]),<ref name="pmid12756210">{{cite journal | vauthors = Zhang W, Ramamoorthy Y, Tyndale RF, Sellers EM | s2cid = 16229370 | title = Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes p450 in vitro | journal = Drug Metabolism and Disposition | volume = 31 | issue = 6 | pages = 768–72 | date = June 2003 | pmid = 12756210 | doi = 10.1124/dmd.31.6.768 }}</ref>
* [[cafestol]] (in unfiltered coffee)<ref>{{cite journal| title = Interaction of coffee diterpenes, cafestol and kahweol, with human P-glycoprotein | vauthors = Nabekura T, Yamaki T, Kitagawa S | date = 2009 | journal = AAPS Journal | publisher = The American Association of Pharmaceutical Scientists | url = http://www.aapsj.org/abstracts/AM_2009/AAPS2009-001235.PDF | archive-url = https://web.archive.org/web/20110721141830/http://www.aapsj.org/abstracts/AM_2009/AAPS2009-001235.PDF | archive-date= 21 July 2011 }}</ref>
* [[cilostazol]],<ref name="FDA-labeling" />
* [[cimetidine]],<ref name="FDA-labeling" />
* [[fosaprepitant]],<ref name="FDA-labeling" />
* [[lomitapide]],<ref name="FDA-labeling" />
* [[orphenadrine]],
* [[omeprazole]]<ref name="Flockhart" /> ([[proton pump inhibitor]]),
* [[quercetin]],<ref name="pmid34601070">{{cite journal |vauthors=Kheoane PS, Enslin GM, Tarirai C |title=Determination of effective concentrations of drug absorption enhancers using in vitro and ex vivo models |journal=Eur J Pharm Sci |volume=167 |issue= |pages=106028 |date=December 2021 |pmid=34601070 |doi=10.1016/j.ejps.2021.106028 |s2cid=238257296 }}</ref><ref name="Flockhart" />
* [[ranitidine]],<ref name="FDA-labeling" />
* [[ranolazine]],<ref name="FDA-labeling" />
* [[tacrolimus]],<ref name="FDA-labeling" />
* [[ticagrelor]],<ref name="FDA-labeling" />
* [[valproic acid]],<ref>{{cite journal | pmc= 2014611 | pmid=11736863 | volume=52 | issue=5 | title=In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9) | journal=Br J Clin Pharmacol | pages=547–53 | vauthors=Wen X, Wang JS, Kivistö KT, Neuvonen PJ, Backman JT | doi=10.1046/j.0306-5251.2001.01474.x| year=2001 }}</ref>
* [[amlodipine]],<ref name="Katoh_2000" />
* [[azithromycin]] ([[macrolide antibiotic]]).<ref name="pmid31628882" />

====Inhibitors of unspecified potency====
* [[bergaptol]] (a [[furocoumarin]] in [[citrus]]),<ref name="pmid38338457">{{cite journal |vauthors=Phucharoenrak P, Trachootham D |title=Bergaptol, a Major Furocoumarin in Citrus: Pharmacological Properties and Toxicity |journal=Molecules |volume=29 |issue=3 |date=February 2024 |page=713 |pmid=38338457 |pmc=10856120 |doi=10.3390/molecules29030713 |doi-access=free }}</ref>
* [[cannabidiol]],<ref name="pmid21356216">{{cite journal | vauthors = Yamaori S, Ebisawa J, Okushima Y, Yamamoto I, Watanabe K | title = Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety | journal = Life Sciences | volume = 88 | issue = 15–16 | pages = 730–6 | date = April 2011 | pmid = 21356216 | doi = 10.1016/j.lfs.2011.02.017 }}</ref>
* [[dithiocarbamate]]<ref name="Flockhart" /> (functional group),
* [[flavonoid]]s,<ref name="pmid38540257">{{cite journal |vauthors=Kondža M, Brizić I, Jokić S |title=Flavonoids as CYP3A4 Inhibitors In Vitro |journal=Biomedicines |volume=12 |issue=3 |date=March 2024 |page=644 |pmid=38540257 |pmc=10968035 |doi=10.3390/biomedicines12030644|doi-access=free }}</ref>
* [[mifepristone]]<ref name="Flockhart" /> ([[abortifacient]]),
* [[norfloxacin]]<ref name="Flockhart" /> ([[Quinolone antibiotic|fluoroquinolone]] antibiotic),
* some non-nucleoside [[reverse-transcriptase inhibitor]]s:<ref name="nnrti">Non-nucleoside reverse-transcriptase inhibitors have been shown to both induce and inhibit CYP3A4.</ref>
** [[delavirdine]];<ref name="Flockhart" />
* [[gestodene]]<ref name="Flockhart" /> ([[hormonal contraceptive]]),
* [[carambola|star fruit]],<ref name="Flockhart" /><ref>{{cite journal | vauthors = Hidaka M, Fujita K, Ogikubo T, Yamasaki K, Iwakiri T, Okumura M, Kodama H, Arimori K | s2cid = 17392051 | title = Potent inhibition by star fruit of human cytochrome P450 3A (CYP3A) activity | journal = Drug Metabolism and Disposition | volume = 32 | issue = 6 | pages = 581–3 | date = June 2004 | pmid = 15155547 | doi = 10.1124/dmd.32.6.581 }}</ref>
* [[milk thistle]],<ref>{{cite web|url=http://www.hcvadvocate.org/hepatitis/hepC/mthistle.html|archiveurl=https://web.archive.org/web/20100305175124/http://www.hcvadvocate.org/hepatitis/hepC/mthistle.html|url-status=dead|title=HCVadvocate.org|archivedate=5 March 2010}}</ref>
* [[Niacin (nutrient)|niacin]]<ref name="Gaudineau_2004">{{cite journal | vauthors = Gaudineau C, Auclair K | title = Inhibition of human P450 enzymes by nicotinic acid and nicotinamide | journal = Biochemical and Biophysical Research Communications | volume = 317 | issue = 3 | pages = 950–6 | date = May 2004 | pmid = 15081432 | doi = 10.1016/j.bbrc.2004.03.137 }}</ref> ([[nicotinic acid]]) and its form – [[niacinamide]] ([[nicotinamide]]), collectively called as Vitamin B<sub>3</sub>,
* [[ginkgo biloba]],<ref name="pmid19883715">{{cite journal | vauthors = Kimura Y, Ito H, Ohnishi R, Hatano T | title = Inhibitory effects of polyphenols on human cytochrome P450 3A4 and 2C9 activity | journal = Food and Chemical Toxicology | volume = 48 | issue = 1 | pages = 429–35 | date = January 2010 | pmid = 19883715 | doi = 10.1016/j.fct.2009.10.041 | quote = Ginko Biloba has been shown to contain the potent inhibitor amentoflavone }}</ref>
* [[sesamin]]<ref name="pmid22645625">{{cite journal | vauthors = Lim YP, Ma CY, Liu CL, Lin YH, Hu ML, Chen JJ, Hung DZ, Hsieh WT, Huang JD | title = Sesamin: A Naturally Occurring Lignan Inhibits CYP3A4 by Antagonizing the Pregnane X Receptor Activation | journal = Evidence-Based Complementary and Alternative Medicine | volume = 2012 | pages = 242810 | year = 2012 | pmid = 22645625 | pmc = 3356939 | doi = 10.1155/2012/242810 | doi-access = free }}</ref> (a [[lignan]] constituent in [[sesame]] seeds and oil),
* [[piperine]],<ref>{{cite journal | vauthors = Bhardwaj RK, Glaeser H, Becquemont L, Klotz U, Gupta SK, Fromm MF | s2cid = 7398172 | title = Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4 | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 302 | issue = 2 | pages = 645–50 | date = August 2002 | pmid = 12130727 | doi = 10.1124/jpet.102.034728 }}</ref>
* [[isoniazid]],<ref>{{cite journal | vauthors = Wen X, Wang JS, Neuvonen PJ, Backman JT | s2cid = 19299097 | title = Isoniazid is a mechanism-based inhibitor of cytochrome P450 1A2, 2A6, 2C19 and 3A4 isoforms in human liver microsomes | journal = European Journal of Clinical Pharmacology | volume = 57 | issue = 11 | pages = 799–804 | date = January 2002 | pmid = 11868802 | doi = 10.1007/s00228-001-0396-3 }}</ref>
* [[serenoa]],<ref>{{cite journal | vauthors = Ekstein D, Schachter SC | title = Natural Products in Epilepsy-the Present Situation and Perspectives for the Future | journal = Pharmaceuticals | volume = 3 | issue = 5 | pages = 1426–1445 | date = May 2010 | pmid = 27713311 | pmc = 4033990 | doi = 10.3390/ph3051426 | doi-access = free }}</ref>
* [[phenelzine]].<ref>{{Cite journal |last=Gillman |first=Peter Kenneth |date=February 2011 |title=Advances pertaining to the pharmacology and interactions of irreversible nonselective monoamine oxidase inhibitors |url=https://pubmed.ncbi.nlm.nih.gov/21192146 |journal=Journal of Clinical Psychopharmacology |volume=31 |issue=1 |pages=66–74 |doi=10.1097/JCP.0b013e31820469ea |issn=1533-712X |pmid=21192146}}</ref>

=== Inducers ===
Strong and moderate CYP3A4 inducers are drugs that decrease the AUC of sensitive substrates of a given pathway where CYP3A4 is involved by ≥80 percent and ≥50 to <80 percent, respectively.<ref name="FDA_drug_development"/><ref name="pmid34526892"/> Weak inducers decrease the AUC by ≥20 to <50 percent.<ref name="pmid34526892">{{cite journal |vauthors=Molenaar-Kuijsten L, Van Balen DE, Beijnen JH, Steeghs N, Huitema AD |title=A Review of CYP3A Drug-Drug Interaction Studies: Practical Guidelines for Patients Using Targeted Oral Anticancer Drugs |journal=Front Pharmacol |volume=12 |issue= |pages=670862 |date=2021 |pmid=34526892 |pmc=8435708 |doi=10.3389/fphar.2021.670862|doi-access=free }}</ref>

The inducers of CYP3A4 are the following substances.

====Strong inducers====
* [[carbamazepine]],<ref name="FDA_drug_development"/><ref name=lange6th>{{cite book | vauthors = Flower R, Rang HP, Dale MM, Ritter JM |title=Rang & Dale's pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2007 |isbn=978-0-443-06911-6 }}{{page needed|date=November 2015}}</ref>
* [[antiandrogen]]s:
** [[enzalutamide]],<ref>{{cite web | title = Highlights of Prescribing Information: XTANDI (enzalutamide) capsules for oral use | url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203415lbl.pdf | author = Astellas Pharma US, Inc. | publisher = U.S. Food and Drug Administration | date = August 2012 | access-date = 10 April 2018 | archive-date = 31 July 2018 | archive-url = https://web.archive.org/web/20180731002946/https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203415lbl.pdf | url-status = dead }}</ref>
** [[apalutamide]];
* [[primidone]]<ref>{{cite journal | vauthors = Schelleman H | title = AExposure to CYP3A4 inducing and CYP3A4 non-inducing antiepileptic agents and the risk of fractures | journal = Pharmacoepidemiol Drug Saf | volume = 20 | issue = 6 | pages = 619–625 | date = Feb 2015| doi =  10.1002/pds.2141 | pmid = 21538673 | pmc = 4340253 }}</ref>
* [[phenytoin]]<ref name="FDA_drug_development"/><ref>{{cite journal | vauthors = Johannessen SI, Landmark CJ | title = Antiepileptic drug interactions - principles and clinical implications | journal = Current Neuropharmacology | volume = 8 | issue = 3 | pages = 254–67 | date = September 2010 | pmid = 21358975 | pmc = 3001218 | doi = 10.2174/157015910792246254 }}</ref> ([[anticonvulsant]]),
* [[rifampin]].<ref name="FDA_drug_development"/>

====Weak inducers====
* [[upadacitinib]].<ref name="Rinvoq-2020" /><ref name="Austria-Codex-DE" />

====Inducers of unspecified potency====
* [[anticonvulsant]]s, [[mood stabilizers]]:
** [[oxcarbazepine]],<ref name=Flockhart/>
** [[topiramate]];<ref>{{cite journal | vauthors = Nallani SC, Glauser TA, Hariparsad N, Setchell K, Buckley DJ, Buckley AR, Desai PB | title = Dose-dependent induction of cytochrome P450 (CYP) 3A4 and activation of pregnane X receptor by topiramate | journal = Epilepsia | volume = 44 | issue = 12 | pages = 1521–8 | date = December 2003 | pmid = 14636322 | doi = 10.1111/j.0013-9580.2003.06203.x | s2cid = 6915760 }}</ref>
* [[barbiturates]]:<ref name=lange6th/>
** [[phenobarbital]],<ref name=Flockhart/><ref name=FASS/>
** [[butalbital]]:
* [[St. John's wort]],<ref name=Flockhart/><ref name=FASS/>
* some [[bactericidal]]s:
** [[rifampicin]],<ref name=Flockhart/><ref name=lange6th/>
** [[rifabutin]];<ref name=Flockhart/><ref name=FASS/>
* some non-nucleoside [[reverse-transcriptase inhibitor]]s:<ref name=nnrti/>
** [[efavirenz]],<ref name=Flockhart/>
** [[nevirapine]];<ref name=Flockhart/>
* [[troglitazone]] ([[hypoglycemic]]),
* [[glucocorticoids]]<ref name=Flockhart/> ([[blood glucose]] increase, [[immunosuppressive]]),
* [[modafinil]]<ref name="pmid34633961" /><ref name=Flockhart/> ([[stimulant]]),
* [[capsaicin]],<ref>{{cite journal | vauthors = Han EH, Kim HG, Choi JH, Jang YJ, Lee SS, Kwon KI, Kim E, Noh K, Jeong TC, Hwang YP, Chung YC, Kang W, Jeong HG | s2cid = 26584141 | title = Capsaicin induces CYP3A4 expression via pregnane X receptor and CCAAT/enhancer-binding protein β activation | journal = Molecular Nutrition & Food Research | volume = 56 | issue = 5 | pages = 797–809 | date = May 2012 | pmid = 22648626 | doi = 10.1002/mnfr.201100697 }}</ref>
* [[brigatinib]],<ref name=Flockhart/>
* [[clobazam]],<ref name=Flockhart/>
* [[dabrafenib]],<ref name=Flockhart/>
* [[elagolix]],<ref name=Flockhart/>
* [[eslicarbazepine]],<ref name=Flockhart/>
* [[letermovir]],<ref name=Flockhart/>
* [[lorlatinib]],<ref name=Flockhart/>
* [[oritavancin]],<ref name=Flockhart/>
* [[perampanel]],<ref name=Flockhart/>
* [[telotristat]].<ref name=Flockhart/>

==Interactive pathway map==
{{IrinotecanPathway_WP229|highlight=CYP3A4}}

== See also ==
* [[List of drugs affected by grapefruit]]

== References ==
{{Reflist|35em}}

== External links ==
* [https://web.archive.org/web/20100415232522/http://www.pharmgkb.org/search/annotatedGene/cyp3a4/index.jsp PharmGKB: Annotated PGx Gene Information for CYP3A4]
* [https://web.archive.org/web/20110215024307/http://p450.althotas.com/ CYP3A4 substrate prediction]
* {{UCSC gene info|CYP3A4}}
* {{PDBe-KB2|P08684|Cytochrome P450 3A4}}

{{NLM content}}
{{PDB Gallery|geneid=1576}}
{{Cytochrome P450}}
{{Dioxygenases}}
{{Enzymes}}
{{Portal bar|Biology|border=no}}

{{DEFAULTSORT:Cyp3a4}}
[[Category:Cytochrome P450|3]]
[[Category:EC 1.14.14]]