Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It
oxidizes small foreign organic molecules (
xenobiotic
A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compo ...
s), such as
toxin
A toxin is a naturally occurring poison produced by metabolic activities of living cells or organisms. They occur especially as proteins, often conjugated. The term was first used by organic chemist Ludwig Brieger (1849–1919), derived ...
s or drugs, so that they can be removed from the body. It is highly homologous to
CYP3A5
Cytochrome P450 3A5 is a protein that in humans is encoded by the ''CYP3A5'' gene.
Tissue distribution
''CYP3A5'' encodes a member of the cytochrome P450 superfamily of enzymes. Like most of the cytochrome P450, the CYP3A5 is expressed in the ...
, 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
The furanocoumarins, or furocoumarins, are a class of organic chemical compounds produced by a variety of plants. Most of the plant species found to contain furanocoumarins belong to a handful of plant families. The families Apiaceae and Rutacea ...
s present in
grapefruit
The grapefruit (''Citrus'' × ''paradisi'') is a subtropical citrus tree known for its relatively large, sour to semi-sweet, somewhat bitter fruit. The flesh of the fruit is segmented and varies in color from pale yellow to dark red.
Grapefru ...
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
Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
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
A hemeprotein (or haemprotein; also hemoprotein or haemoprotein), or heme protein, is a protein that contains a heme prosthetic group. They are a very large class of metalloproteins. The heme group confers functionality, which can include oxygen ...
, i.e. a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
containing a
heme
Heme (American English), or haem (Commonwealth English, both pronounced /Help:IPA/English, hi:m/ ), is a ring-shaped iron-containing molecule that commonly serves as a Ligand (biochemistry), ligand of various proteins, more notably as a Prostheti ...
group with an iron atom. In humans, the CYP3A4 protein is encoded by the ''CYP3A4''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
This gene is part of a cluster of cytochrome P450 genes on
chromosome 7q22.1.
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.
Function
CYP3A4 is a member of the
cytochrome P450
Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
superfamily of
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
s. The cytochrome P450 proteins are
monooxygenase
Monooxygenases are enzymes that incorporate one hydroxyl group (−OH) into substrates in many metabolic pathways. In this reaction, the two atoms of dioxygen are reduced to one hydroxyl group and one H2O molecule by the concomitant oxidation of ...
s that catalyze many reactions involved in
drug metabolism
Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism (from the Greek xenos "stranger" and biotic "related to living beings") is the set o ...
and synthesis of
steroid
A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration.
Steroids have two principal biological functions: as important components of cell membranes t ...
s (including
cholesterol
Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils.
Cholesterol is biosynthesis, biosynthesized by all anima ...
), and other
lipid
Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...
s.
The CYP3A4 protein localizes to the
endoplasmic reticulum
The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...
, and its expression is induced by
glucocorticoid
Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebra ...
s and some pharmacological agents.
Cytochrome P450 enzymes metabolize approximately 60% of prescribed drugs, with CYP3A4 responsible for about half of this metabolism; substrates include
acetaminophen (paracetamol),
codeine
Codeine is an opiate and prodrug of morphine mainly used to treat pain, coughing, and diarrhea. It is also commonly used as a recreational drug. It is found naturally in the sap of the opium poppy, ''Papaver somniferum''. It is typically use ...
,
ciclosporin
Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken Oral administration, orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephr ...
(cyclosporin),
diazepam
Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety disorder, anxiety, seizures, alcohol withdrawal syndr ...
,
erythromycin
Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used ...
, and
chloroquine
Chloroquine is an antiparasitic medication that treats malaria. It works by increasing the levels of heme in the blood, a substance toxic to the malarial parasite. This kills the parasite and stops the infection from spreading. Certain types ...
.
The enzyme also metabolizes some
steroid
A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration.
Steroids have two principal biological functions: as important components of cell membranes t ...
s and
carcinogen
A carcinogen () is any agent that promotes the development of cancer. Carcinogens can include synthetic chemicals, naturally occurring substances, physical agents such as ionizing and non-ionizing radiation, and biologic agents such as viruse ...
s.
Most drugs undergo deactivation by CYP3A4, either directly or by facilitated
excretion
Excretion is elimination of metabolic waste, which is an essential process in all organisms. In vertebrates, this is primarily carried out by the lungs, Kidney (vertebrates), kidneys, and skin. This is in contrast with secretion, where the substa ...
from the body. Also, many substances are
bioactivated by CYP3A4 to form their active compounds, and many protoxins are
toxicated
Toxication, toxification or toxicity exaltation is the conversion of a chemical compound into a more toxic form in living organisms or in substrates such as soil or water. The conversion can be caused by enzyme, enzymatic metabolism in the organism ...
into their toxic forms ''(see table below for examples)''.
CYP3A4 also possesses
epoxygenase
Epoxygenases are a set of membrane-bound, heme-containing cytochrome P450 (CYP450 or just CYP) enzymes that metabolize polyunsaturated fatty acids (PUFAs) to epoxide products that have a range of biological activities.
The most thoroughly-studi ...
activity in that it metabolizes
arachidonic acid
Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega−6 fatty acid 20:4(ω−6), or 20:4(5,8,11,14). It is a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes.
Together with omega−3 fatty acids an ...
to
epoxyeicosatrienoic acid
The epoxyeicosatrienoic acids or EETs are signaling molecules formed within various types of cells by the metabolism of arachidonic acid by a specific subset of cytochrome P450 enzymes, termed cytochrome P450 epoxygenases. They are nonclassic e ...
s (EETs), i.e. (±)-8,9-, (±)-11,12-, and (±)-14,15-epoxyeicosatrienoic acids. EETs have a wide range of activities including the promotion of certain types of
cancer
Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
s (see
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. The CYP3A4 enzyme is also reported to have fatty acid monooxgenase activity for metabolizing arachidonic acid to
20-Hydroxyeicosatetraenoic acid (20-HETE).
20-HETE has a wide range of activities that include growth stimulation in breast and other types of cancers (see
12-hydroxyeicosatetraenoic acid).
Evolution
The ''CYP3A4'' gene exhibits a much more complicated upstream regulatory region in comparison with its
paralogs.
This increased complexity renders the ''CYP3A4'' gene more sensitive to endogenous and exogenous
pregnane X receptor (PXR) and
constitutive androstane receptor
The constitutive androstane receptor (CAR) also known as nuclear receptor subfamily 1, group I, member 3 is a protein that in humans is encoded by the ''NR1I3'' gene. CAR is a member of the nuclear receptor superfamily and along with pregnane ...
(CAR) ligands, instead of relying on gene variants for wider specificity.
Chimpanzee
The chimpanzee (; ''Pan troglodytes''), also simply known as the chimp, is a species of Hominidae, great ape native to the forests and savannahs of tropical Africa. It has four confirmed subspecies and a fifth proposed one. When its close rel ...
and human CYP3A4 are highly conserved in metabolism of many
ligands
In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ...
, 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
Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver in peroxisomes. Bile acids are conjugated with taurine or glycine residues to give anions called bile ...
lithocholic acid.
This change in consequence contributes to an increased human defense against
cholestasis
Cholestasis is a condition where the flow of bile from the liver to the duodenum is impaired. The two basic distinctions are:
* obstructive type of cholestasis, where there is a mechanical blockage in the duct system that can occur from a gallston ...
.
Tissue distribution
Fetus
A fetus or foetus (; : fetuses, foetuses, rarely feti or foeti) is the unborn offspring of a viviparous animal that develops from an embryo. Following the embryonic development, embryonic stage, the fetal stage of development takes place. Pren ...
es do not express ''CYP3A4'' in their liver tissue, but rather ''
CYP3A7
CYP3A7 is an enzyme belonging to the cytochrome P450 family. It is 503 amino acids in size and shares 87% of its sequence with CYP3A4. It carries out a similar role in fetuses that CYP3A4 serves in adults. The gene location is 7q22.1.
The CYP3A ...
'' (), 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.
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.
CYP3A4 in the intestine plays an important role in the metabolism of certain drugs. Often this allows
prodrug
A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...
s to be activated and absorbed, as in the case of the
histamine H1-receptor antagonist terfenadine
Terfenadine is an antihistamine formerly used for the treatment of allergic conditions. It was brought to market by Hoechst Marion Roussel (now Sanofi) and was marketed under various brand names, including Seldane in the United States, Triluda ...
.
CYP3A4 has also been identified in the brain, but its role in the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
is unknown.
Mechanisms
Cytochrome P450
Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
enzymes perform an assortment of modifications on a variety of
ligand
In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...
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
In chemistry, hydroxylation refers to the installation of a hydroxyl group () into an organic compound. Hydroxylations generate alcohols and phenols, which are very common functional groups. Hydroxylation confers some degree of water-solubility ...
,
epoxidation
In organic chemistry, an epoxide is a cyclic ether, where the ether forms a three-atom ring: two atoms of carbon and one atom of oxygen. This triangular structure has substantial ring strain, making epoxides highly reactive, more so than other ...
of
olefins
In organic chemistry, an alkene, or olefin, is a hydrocarbon containing a carbon–carbon double bond. The double bond may be internal or at the terminal position. Terminal alkenes are also known as α-olefins.
The International Union of P ...
, aromatic
oxidation
Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...
, heteroatom oxidations, N- and O- dealkylation reactions, aldehyde oxidations,
dehydrogenation reactions, and aromatase activity.
Hydroxylation of an
sp3 C-H bond is one of the ways in which CYP3A4 (and cytochrome P450 oxygenases) affects its ligand.
In fact, hydroxylation is sometimes followed by dehydrogenation, leading to more complex metabolites.
An example of a molecule that undergoes more than one reaction due to CYP3A4 includes
tamoxifen
Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome ...
, which is hydroxylated to 4-hydroxy-tamoxifen and then dehydrated to 4-hydroxy-tamoxifen quinone methide.
Two mechanisms have been proposed as the primary pathway of hydroxylation in P450 enzymes.

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".
Inhibition through fruit ingestion
In 1998, various researchers showed that
grapefruit
The grapefruit (''Citrus'' × ''paradisi'') is a subtropical citrus tree known for its relatively large, sour to semi-sweet, somewhat bitter fruit. The flesh of the fruit is segmented and varies in color from pale yellow to dark red.
Grapefru ...
juice, and grapefruit in general, is a potent inhibitor of CYP3A4, which can affect the metabolism of a variety of drugs, increasing their
bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.
By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...
.
In some cases, this can lead to a fatal interaction with drugs like
astemizole or
terfenadine
Terfenadine is an antihistamine formerly used for the treatment of allergic conditions. It was brought to market by Hoechst Marion Roussel (now Sanofi) and was marketed under various brand names, including Seldane in the United States, Triluda ...
.
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
Nifedipine ( ), sold under the brand name Procardia among others, is a calcium channel blocker medication used to manage angina, high blood pressure, Raynaud's phenomenon, and premature labor. It is one of the treatments of choice for Prinzme ...
", 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.
In addition to grapefruit, other fruits have similar effects.
Noni
''Morinda citrifolia'' is a fruit-bearing tree in the coffee family, Rubiaceae, native to Southeast Asia and Australasia, which was spread across the Pacific by Polynesian sailors. The species is now cultivated throughout the tropics and widel ...
(''Morinda citrifolia''), for example, is a
dietary supplement
A dietary supplement is a manufactured product intended to supplement a person's diet by taking a pill (pharmacy), pill, capsule (pharmacy), capsule, tablet (pharmacy), tablet, powder, or liquid. A supplement can provide nutrients eithe ...
typically consumed as a juice and also inhibits CYP3A4.
Pomegranate
The pomegranate (''Punica granatum'') is a fruit-bearing deciduous shrub in the family Lythraceae, subfamily Punica, Punicoideae, that grows between tall. Rich in symbolic and mythological associations in many cultures, it is thought to have o ...
juice has shown some inhibition in limited studies, but has not yet demonstrated the effect in humans.
Variability
While over 28
single nucleotide polymorphism
In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...
s (SNPs) have been identified in the ''CYP3A4'' gene, it has been found that this does not translate into significant interindividual variability . 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
Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...
and
nifedipine
Nifedipine ( ), sold under the brand name Procardia among others, is a calcium channel blocker medication used to manage angina, high blood pressure, Raynaud's phenomenon, and premature labor. It is one of the treatments of choice for Prinzme ...
in comparison to wild-type metabolism.
By contrast, ''CYP3A4*1G'' allele has more potent enzymatic activity compared to ''CYP3A4*1A'' (the wild-type allele).
[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.]
Variability in CYP3A4 function can be determined noninvasively by the
erythromycin breath test (ERMBT). The ERMBT estimates CYP3A4 activity by measuring the radiolabelled carbon dioxide exhaled after an intravenous dose of (
14C-''N''-methyl)-
erythromycin
Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used ...
.
Induction
CYP3A4 is
induced by a wide variety of
ligand
In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...
s. These ligands bind to the
pregnane X receptor (PXR). The activated PXR complex forms a heterodimer with the
retinoid X receptor
The retinoid X receptor (RXR) is a type of nuclear receptor that is activated by 9-cis retinoic acid, which is discussed controversially to be of endogenous relevance, and 9-''cis''-13,14-dihydroretinoic acid, which may be an endogenous mamma ...
(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 of the CYP3A4 promoter region and gene. Ligand binding increases when in the presence of CYP3A4 ligands, such as in the presence of
aflatoxin
Aflatoxins are various toxicity, poisonous carcinogens and mutagens that are produced by certain Mold (fungus), molds, especially ''Aspergillus'' species such as ''Aspergillus flavus'' and ''Aspergillus parasiticus''. According to the USDA, "The ...
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.
Induction of CYP3A4 has been shown to vary in humans depending on sex. Evidence shows an increased
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
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
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.
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
Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), ''Mycobacterium avium'' complex, leprosy, and Legionnaires' disease. It is almost always used tog ...
and human PXR is not activated by pregnenolone 16α-carbonitrile
In order to facilitate study of CYP3A4 functional pathways ''in vivo,'' mouse strains have been developed using
transgene
A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the ...
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.
This effect has been attributed to CYP3A4 regulation by the
growth hormone
Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in ...
signal transduction pathway.
In addition to providing an ''in vivo'' model, humanized CYP3A4 mice (hCYP3A4) have been used to further emphasize gender differences in CYP3A4 activity.
CYP3A4 activity levels have also been linked to diet and environmental factors, such as duration of exposure to xenobiotic substances.
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.
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
turnover rate of human CYP3A4 vary widely. For hepatic CYP3A4, ''in vivo'' methods yield estimates of the enzyme
half-life Half-life is a mathematical and scientific description of exponential or gradual decay.
Half-life, half life or halflife may also refer to:
Film
* Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang
* ''Half Life: ...
mainly in the range of 70 to 140 hours, whereas ''in vitro'' methods give estimates from 26 to 79 hours.
Turnover of gut CYP3A4 is likely to be a function of the rate of
enterocyte
Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase ...
renewal; an indirect approach based on the recovery of activity following exposure to grapefruit juice yields measurements in the 12- to 33-hour range.
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
KD (between 5–150 μM) and low solubility in aqueous solutions.
A successful strategy in isolating the bound enzyme is the functional stabilization of monomeric CYP3A4 on silver
nanoparticle
A nanoparticle or ultrafine particle is a particle of matter 1 to 100 nanometres (nm) in diameter. The term is sometimes used for larger particles, up to 500 nm, or fibers and tubes that are less than 100 nm in only two directions. At ...
s produced from
nanosphere lithography and analyzed via localized
surface plasmon resonance
Surface plasmon resonance (SPR) is a phenomenon that occurs where electrons in a thin metal sheet become excited by light that is directed to the sheet with a particular angle of incidence (optics), angle of incidence, and then travel parallel to ...
spectroscopy (LSPR).
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 NMR
Solid-state nuclear magnetic resonance (ssNMR) is a spectroscopy technique used to characterize atomic-level structure and dynamics in solid materials. ssNMR spectra are broader due to nuclear spin interactions which can be categorized as dipolar ...
, redox potentiometry, and
steady-state enzyme kinetics.
Ligands
Following are lists of selected
substrates,
inducers and
inhibitors of CYP3A4. Where classes of agents are listed, there may be exceptions within the class.
Substrates
The substrates of CYP3A4 are:
* some
immunosuppressant
Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system.
Classification
Immunosuppressive drugs can be classified ...
s:
**
ciclosporin
Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken Oral administration, orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephr ...
(cyclosporin),
FASS (drug formulary)
A formulary is a list of pharmaceutical drugs, often decided upon by a group of people, for various reasons such as insurance coverage or use at a medical facility. Traditionally, a formulary contained a collection of formulas for the compounding ...
Swedish environmental classification of pharmaceuticals
Facts for prescribers (Fakta för förskrivare). Retrieved July 2011
** tacrolimus
Tacrolimus, sold under the brand name Prograf among others, is an immunosuppressive drug. After Allotransplantation, allogenic organ transplant, the risk of organ Transplant rejection, rejection is moderate. To lower the risk of organ rejectio ...
,[
** sirolimus,][
** upadacitinib;][Rinvoq: EPAR – Public assessment report]
" (PDF). European Medicines Agency
The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...
. 5 March 2020. Archived (PDF) from the original on 21 July 2020. Retrieved 21 July 2020.[''Austria-Codex'' (in German). Vienna: Österreichischer Apothekerverlag. 2020. Rinvoq 15 mg Retardtabletten.]
* many chemotherapeutics:
** docetaxel
Docetaxel (DTX or DXL), sold under the brand name Taxotere among others, is a chemotherapy medication used to treat a number of types of cancer. This includes breast cancer, head and neck cancer, stomach cancer, prostate cancer and non-small-cel ...
,[
** ]tamoxifen
Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome ...
,[
** ]paclitaxel
Paclitaxel, sold under the brand name Taxol among others, is a chemotherapy medication used to treat ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer, and pancreatic cancer. It is administered b ...
,[
** ]cyclophosphamide
Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer ...
,[
** ]doxorubicin
Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used toge ...
,[
** erlotinib,
** ]etoposide
Etoposide, sold under the brand name Vepesid among others, is a chemotherapy medication used for the treatments of a number of types of cancer including testicular cancer, lung cancer, lymphoma, leukemia, neuroblastoma, and ovarian cancer. It is ...
,[
** ifosfamide,][
** teniposide,][
** ]vinblastine
Vinblastine, sold under the brand name Velban among others, is a chemotherapy medication, typically used with other medications, to treat a number of types of cancer. This includes Hodgkin's lymphoma, non-small-cell lung cancer, bladder canc ...
,[
** ]vincristine
Vincristine, also known as leurocristine and sold under the brand name Oncovin among others, is a chemotherapy medication used to treat a number of types of cancer. This includes acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin lym ...
,[
** ]vindesine
Vindesine, also termed Eldisine, is a semisynthetic vinca alkaloid derived from the flowering plant '' Catharanthus roseus.'' Like the natural (e.g. vinblastine and vincristine) and semisynthetic vinca alkaloids (e.g. vinorelbine and vinflunine ...
,[
** ]imatinib
Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral targeted therapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple tyrosine kinases ...
,[
** ]irinotecan
Irinotecan, sold under the brand name Camptosar among others, is an anti-cancer medication used to treat colon cancer and small cell lung cancer. For colon cancer it is used either alone or with fluorouracil. For small cell lung cancer it is ...
,[
** sorafenib,][
** sunitinib,][
** ]vemurafenib
Vemurafenib ( INN), sold under the brand name Zelboraf, is a medication used for the treatment of late-stage melanoma.; It is an inhibitor of the B-Raf enzyme and was developed by Plexxikon.
Mechanism of action
Vemurafenib causes programm ...
,[
** ]temsirolimus
Temsirolimus, sold under the brand name Torisel, is an intravenous drug for the treatment of renal cell carcinoma (RCC), developed by Wyeth Pharmaceuticals and approved by the U.S. Food and Drug Administration (FDA) in May 2007, and was also app ...
,[
** ]anastrozole
Anastrozole, sold under the brand name Arimidex among others, is an antiestrogenic medication used in addition to other treatments for breast cancer. Specifically it is used for hormone receptor-positive breast cancer. It has also been used t ...
,
** gefitinib
Gefitinib, sold under the brand name Iressa, is a medication used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in targe ...
;
* azole antifungals:
** ketoconazole
Ketoconazole, sold under the brand name Nizoral, among others, is an antiandrogen, antifungal drug, antifungal, and antiglucocorticoid medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin inf ...
[
** ]itraconazole
Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given ...
[
* ]macrolide
Macrolides are a class of mostly natural products with a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. Macrolides belong to the polyketide class of natural products. ...
s (except azithromycin
Azithromycin, sold under the brand names Zithromax (in oral form) and Azasite (as an eye drop), is an antibiotic medication used for the treatment of several bacterial infections. This includes otitis media, middle ear infections, strep throa ...
):
** clarithromycin
Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, '' H. pylori'' infection, and Lyme disease, among others. Clari ...
,
** erythromycin
Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used ...
,
** telithromycin;
* dapsone
Dapsone, also known as 4,4'-sulfonyldianiline (SDA) or diaminodiphenyl sulfone (DDS), is an antibiotic commonly used in combination with rifampicin and clofazimine for the treatment of leprosy. It is a second-line medication for the treatment an ...
[ (in ]leprosy
Leprosy, also known as Hansen's disease (HD), is a Chronic condition, long-term infection by the bacteria ''Mycobacterium leprae'' or ''Mycobacterium lepromatosis''. Infection can lead to damage of the Peripheral nervous system, nerves, respir ...
),
* tricyclic antidepressants
Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains ...
:
** amitriptyline
Amitriptyline, sold under the brand name Elavil among others, is a tricyclic antidepressant primarily used to treat major depressive disorder, and a variety of pain syndromes such as neuropathic pain, fibromyalgia, migraine and tension headac ...
,[
** ]clomipramine
Clomipramine, sold under the brand name Anafranil among others, is a tricyclic antidepressant (TCA). It is used in the treatment of various conditions, most notably obsessive–compulsive disorder but also many other disorders, including hyper ...
,[
** ]imipramine
Imipramine, sold under the brand name Tofranil, among others, is a tricyclic antidepressant (TCA) mainly used in the treatment of depression. It is also effective in treating anxiety and panic disorder. Imipramine is taken by mouth.
Common s ...
,[
** ]cyclobenzaprine
Cyclobenzaprine, sold under several brand names including, historically, Flexeril, is a muscle relaxer used for muscle spasms from musculoskeletal conditions of sudden onset. It is not useful in cerebral palsy. It is taken by mouth.
Common ...
;
* SSRI antidepressants :
** citalopram
Citalopram, sold under the brand name Celexa among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive compulsive disorder, panic disorder, and soci ...
[
** norfluoxetine][
** ]sertraline
Sertraline, sold under the brand name Zoloft among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used to treat major depressive disorder, generalized anxiety disorder, socia ...
[
* some other antidepressants:
** ]mirtazapine
Mirtazapine, sold under the brand name Remeron among others, is an atypical antidepressant, atypical tetracyclic antidepressant, and as such is used primarily to treat Depression (mood), depression. Its effects may take up to four weeks but ca ...
[ ( NaSSA),
** nefazodone][ (]atypical
''Atypical'' is an American comedy-drama television series created by Robia Rashid for Netflix. The series takes place in Connecticut, and focuses on the life of 18-year-old Samuel "Sam" Gardner ( Keir Gilchrist), who is autistic. The first sea ...
),
** reboxetine[ ( NRI),
** ]venlafaxine
Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin–norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, pani ...
[ ( SNRI),
** ]trazodone
Trazodone is an antidepressant medication used to treat major depressive disorder, anxiety disorders, and insomnia. It is a phenylpiperazine compound of the serotonin antagonist and reuptake inhibitor (SARI) class. The medication is taken or ...
[ (]SARI
A sari (also called sharee, saree or sadi)The name of the garment in various regional languages include:
*
*
*
*
*
*
*
*
*
*
*
*
*
* is a drape (cloth) and a women's garment in the Indian subcontinent. It consists of an un-sti ...
),
** vilazodone[ ( serotonin modulator),
* ]buspirone
Buspirone, sold under the brand name Buspar among others, is an anxiolytic, a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder (GAD). It is a serotonin 5-HT1A receptor, 5-HT1A receptor partial ag ...
[ (]anxiolytic
An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...
),
* antipsychotics
Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizo ...
:
** haloperidol
Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychos ...
,[
** ]aripiprazole
Aripiprazole, sold under the brand name Abilify, among others, is an atypical antipsychotic primarily used in the treatment of schizophrenia, bipolar disorder, and irritability associated with autism spectrum disorder; other uses include as ...
,[
** ]risperidone
Risperidone, sold under the brand name Risperdal among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder, as well as aggressive and self-injurious behaviors associated with autism spectrum disorder. It is t ...
,[
** ziprasidone,][
** ]pimozide
Pimozide (sold under the brand name Orap) is a neuroleptic medication, drug of the diphenylbutylpiperidine class. It was discovered at Janssen Pharmaceutica in 1963. It has a high potency compared to chlorpromazine (ratio 50-70:1). On a weigh ...
,[
** quetiapine,][
** lurasidone;
* ]opioids
Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...
(mainly analgesics):
** alfentanil,[
** buprenorphine] (analgesic
An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...
, addiction maintenance treatment),
** codeine
Codeine is an opiate and prodrug of morphine mainly used to treat pain, coughing, and diarrhea. It is also commonly used as a recreational drug. It is found naturally in the sap of the opium poppy, ''Papaver somniferum''. It is typically use ...
[ (]analgesic
An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...
, antitussive, antidiarrheal),
** fentanyl
Fentanyl is a highly potent synthetic piperidine opioid primarily used as an analgesic (pain medication). It is 30 to 50 times more Potency (pharmacology), potent than heroin and 50 to 100 times more potent than morphine. Its primary Medici ...
,[
** ]hydrocodone
Hydrocodone, also known as dihydrocodeinone, is a semi-synthetic opioid used to treat pain and as a cough suppressant. It is taken by mouth. Typically, it is dispensed as the combination acetaminophen/hydrocodone or ibuprofen/hydrocodone fo ...
(partial involvement, not the bioactivation factor),
** methadone
Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid used medically to treat chronic pain and opioid use disorder. Prescribed for daily use, the medicine relieves cravings and opioid withdrawal sym ...
[ (]analgesic
An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...
, addiction maintenance treatment),
** levacetylmethadol,[
** ]tramadol
Tramadol, sold under the brand name Tramal among others, is an opioid analgesic, pain medication and a serotonin–norepinephrine reuptake inhibitor (SNRI) used to treat moderately severe pain. When taken by mouth in an immediate-release form ...
(analgesic
An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...
, refractory
In materials science, a refractory (or refractory material) is a material that is resistant to decomposition by heat or chemical attack and that retains its strength and rigidity at high temperatures. They are inorganic, non-metallic compound ...
RLS treatment);
* benzodiazepines
Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat co ...
:
** alprazolam
Alprazolam, sold under the brand name Xanax among others, is a fast-acting, potent tranquilizer of moderate duration within the triazolobenzodiazepine group of chemicals called benzodiazepines. Alprazolam is most commonly prescribed in the ...
,[
** ]midazolam
Midazolam, sold under the brand name Versed among others, is a benzodiazepine medication used for anesthesia, premedication before surgical anesthesia, and procedural sedation, and to treat psychomotor agitation, severe agitation. It induces ...
,[
** ]triazolam
Triazolam, sold under the brand name Halcion among others, is a central nervous system (CNS) depressant tranquilizer of the triazolobenzodiazepine (TBZD) class, which are benzodiazepine (BZD) derivatives. It possesses pharmacological properti ...
,[
** ]diazepam
Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety disorder, anxiety, seizures, alcohol withdrawal syndr ...
,[ (bioactivation to ]desmethyldiazepam
Nordazepam ( INN; marketed under brand names Nordaz, Stilny, Madar, Vegesan, and Calmday; also known as nordiazepam, desoxydemoxepam, and desmethyldiazepam) is a 1,4-benzodiazepine derivative. Like other benzodiazepine derivatives, it has amnes ...
)
** clonazepam
Clonazepam, sold under the brand name Klonopin among others, is a benzodiazepine medication used to prevent and treat anxiety disorders, seizures, bipolar mania, agitation associated with psychosis, obsessive–compulsive disorder (OCD), and ...
;
* some hypnotic
A hypnotic (from Ancient Greek, Greek ''Hypnos'', sleep), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to sleep induction, induce sleep and to trea ...
s:
** zopiclone,[
** zaleplon,][
** zolpidem,][
* donepezil][ (acetylcholinesterase inhibitor),
* statins (except pravastatin] and rosuvastatin):
** atorvastatin,
** lovastatin,
** simvastatin,
** cerivastatin;
* calcium channel blockers:
** diltiazem[ (sensitive substrate]),
** felodipine[ (sensitive substrate]),
** nifedipine
Nifedipine ( ), sold under the brand name Procardia among others, is a calcium channel blocker medication used to manage angina, high blood pressure, Raynaud's phenomenon, and premature labor. It is one of the treatments of choice for Prinzme ...
[ (sensitive substrate]),
** verapamil[ (sensitive substrate]),
** amlodipine[ (sensitive substrate]),
** lercanidipine,[
** nitrendipine,][
** nisoldipine,][
* amiodarone][ (class III antiarrhythmic),
* dronedarone][ (class III antiarrhythmic),
* quinidine][ (class I antiarrhythmic agent, class I antiarrhythmic),
* PDE5 inhibitors:
** sildenafil,][
** tadalafil,
* kinins][ (vasodilators, smooth muscle contractors),
* ]steroid
A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration.
Steroids have two principal biological functions: as important components of cell membranes t ...
s:
** sex hormones (agonists and antagonists):
*** finasteride[ (antiandrogen),
*** estradiol][ (estrogen),
*** progesterone,][
*** ethinylestradiol][ (hormonal contraceptive),
*** ]testosterone
Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...
[ (androgen),
*** toremifene][ (selective estrogen receptor modulator, SERM),
*** bicalutamide;]
** glucocorticoid
Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebra ...
s:
*** budesonide,[
*** hydrocortisone (cortisol),]
*** dexamethasone,[
*** fluticasone;
* some H1-receptor antagonist, H1-receptor antagonists (H1 antihistamines):
** ketotifen,]
** terfenadine
Terfenadine is an antihistamine formerly used for the treatment of allergic conditions. It was brought to market by Hoechst Marion Roussel (now Sanofi) and was marketed under various brand names, including Seldane in the United States, Triluda ...
,
** astemizole,
** chlorphenamine;
* protease inhibitors:
** indinavir,[
** ritonavir,][
** saquinavir,][
** nelfinavir;][
* non-nucleoside reverse-transcriptase inhibitors (antiretroviral drugs):
** nevirapine]
** delavirdine,
** efavirenz,
** etravirine,
** rilpivirine;
* albendazole (antihelminthic)
* cisapride,[ (5-HT4 receptor agonist)
* aprepitant,][ (antiemetic)
* caffeine,][ (stimulant)
* cocaine,][ (stimulant)
* cilostazol,][ (phosphodiesterase inhibitor)
* dextromethorphan,][ ( antitussive)
* domperidone,][ (antidopaminergic)
* eplerenone,][ (aldosterone antagonist)
* lidocaine,][ (local anesthetic, antiarrhythmic)
* ondansetron,][ (5-HT3 antagonist)
* propranolol,][ (beta blocker)
* salmeterol,][ (beta agonist)
* warfarin,] (anticoagulant)
* clopidogrel becoming bioactivated (antiplatelet agent, antiplatelet),
* 2-oxo-clopidogrel,
* omeprazole,[ (proton pump inhibitor)
* nateglinide,][ (antidiabetic)
* methoxetamine,]
* montelukast (leukotriene receptor antagonist),
* vilaprisan (selective progesterone receptor modulator),
* certain angiotensin II receptor blockers:
** losartan (sensitive substrates)
** irbesartan.
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.[
* a Moderate inhibitor causes at least a 2-fold increase in the plasma AUC values, or 50–80% decrease in clearance.][
* 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.][ Retrieved on 25 December 2008.]
The inhibitors of CYP3A4 are the following substances.
Strong inhibitors
* boceprevir,
* Pharmacologic protease inhibitor, protease inhibitors:
** ritonavir,
** indinavir,
** nelfinavir,
** saquinavir;
* some Macrolide, macrolide antibiotics:
** clarithromycin
Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, '' H. pylori'' infection, and Lyme disease, among others. Clari ...
,
** erythromycin
Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used ...
(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);
** telithromycin
* ceritinib
* mibefradil (used for the treatment of hypertension and chronic angina pectoris)
* nefazodone (antidepressant)
* ribociclib
* tucatinib
* chloramphenicol (antibiotic)
* some azole antifungals:
** ketoconazole
Ketoconazole, sold under the brand name Nizoral, among others, is an antiandrogen, antifungal drug, antifungal, and antiglucocorticoid medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin inf ...
,
** itraconazole
Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given ...
,
** posaconazole,
** voriconazole;
* cobicistat,
* green tea extract,
* grape seed extract,
* dillapiole (compound present in dill plants),
* apigenin (compound present in plants such as celery, parsley, and chamomile)
* ''Artemisia annua''
Moderate inhibitors
* amiodarone (class III antiarrhythmic),
* aprepitant, (antiemetic)
* ciprofloxacin,
* conivaptan,
* crizotinib,
* rutin ''(in vitro)'' (dietary flavonoid),
* tofisopam,
* some calcium channel blockers:
** verapamil,
** diltiazem;
* some azole antifungals:
** fluconazole,
** miconazole;
* bergamottin (constituent of grapefruit
The grapefruit (''Citrus'' × ''paradisi'') is a subtropical citrus tree known for its relatively large, sour to semi-sweet, somewhat bitter fruit. The flesh of the fruit is segmented and varies in color from pale yellow to dark red.
Grapefru ...
juice),
* Ciclosporin, cyclosporine,
* Dronedarone, donedarone,
* fluvoxamine,
* imatinib
Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral targeted therapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple tyrosine kinases ...
,
* Valerian (herb), valerian.
Weak inhibitors
* berberine (an alkaloid found in plants such as berberis or goldenseal),
* buprenorphine (analgesic
An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...
),
* cafestol (in unfiltered coffee)
* cilostazol,
* cimetidine,
* fosaprepitant,
* lomitapide,
* orphenadrine,
* omeprazole (proton pump inhibitor),
* quercetin,
* ranitidine,
* ranolazine,
* tacrolimus
Tacrolimus, sold under the brand name Prograf among others, is an immunosuppressive drug. After Allotransplantation, allogenic organ transplant, the risk of organ Transplant rejection, rejection is moderate. To lower the risk of organ rejectio ...
,
* ticagrelor,
* valproic acid,
* amlodipine,
* azithromycin
Azithromycin, sold under the brand names Zithromax (in oral form) and Azasite (as an eye drop), is an antibiotic medication used for the treatment of several bacterial infections. This includes otitis media, middle ear infections, strep throa ...
(macrolide antibiotic).
Inhibitors of unspecified potency
* bergaptol (a furocoumarin in citrus),
* cannabidiol,
* dithiocarbamate (functional group),
* flavonoids,
* mifepristone (abortifacient),
* norfloxacin (Quinolone antibiotic, fluoroquinolone antibiotic),
* some non-nucleoside reverse-transcriptase inhibitors:[Non-nucleoside reverse-transcriptase inhibitors have been shown to both induce and inhibit CYP3A4.]
** delavirdine;
* gestodene (hormonal contraceptive),
* carambola, star fruit,
* milk thistle,
* Niacin (nutrient), niacin (nicotinic acid) and its form – niacinamide (nicotinamide), collectively called as Vitamin B3,
* ginkgo biloba,
* sesamin (a lignan constituent in sesame seeds and oil),
* piperine,
* isoniazid,
* serenoa,
* phenelzine.
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. Weak inducers decrease the AUC by ≥20 to <50 percent.
The inducers of CYP3A4 are the following substances.
Strong inducers
* carbamazepine,
* antiandrogens:
** enzalutamide,
** apalutamide;
* primidone
* phenytoin (anticonvulsant),
* rifampin.
Weak inducers
* upadacitinib.
Inducers of unspecified potency
* anticonvulsants, mood stabilizers:
** oxcarbazepine,[
** topiramate;
* barbiturates:][
** phenobarbital,][
** butalbital:
* St. John's wort,][
* some bactericidals:
** ]rifampicin
Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), ''Mycobacterium avium'' complex, leprosy, and Legionnaires' disease. It is almost always used tog ...
,[
** rifabutin;][
* some non-nucleoside reverse-transcriptase inhibitors:][
** efavirenz,][
** nevirapine;][
* troglitazone (hypoglycemic),
* glucocorticoids][ (blood glucose increase, immunosuppressive),
* modafinil][ (stimulant),
* capsaicin,]
* brigatinib,[
* clobazam,][
* dabrafenib,][
* elagolix,][
* eslicarbazepine,][
* letermovir,][
* lorlatinib,][
* oritavancin,][
* perampanel,][
* telotristat.][
]
Interactive pathway map
See also
* List of drugs affected by grapefruit
References
External links
PharmGKB: Annotated PGx Gene Information for CYP3A4
CYP3A4 substrate prediction
*
*
{{DEFAULTSORT:Cyp3a4
Cytochrome P450, 3
EC 1.14.14