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Identification
- Summary
Levoketoconazole is one of two enantiomeric forms of racemic ketoconazole that strongly inhibits multiple steroidogenic enzymes and is used for the symptomatic treatment of endogenous Cushing's syndrome.
- Brand Names
- Recorlev
- Generic Name
- Levoketoconazole
- DrugBank Accession Number
- DB05667
- Background
Cushing's syndrome (CS) is underpinned by chronic hypercortisolism leading to multisystem morbidity, including effects on the cardiovascular and endocrine systems, metabolic syndrome with accompanying changes in body composition, neuropsychiatric effects, changes in blood pressure and chemistry, and opportunistic infections.1,2 Ketoconazole has been used both on- and off-label to treat CS due to its ability to inhibit cortisol production. Still, toxicity has limited its use, notably hepatic toxicity and a tendency to prolong the QT interval.2 Levoketoconazole is one of two enantiomers present in racemic ketoconazole. It possesses most of the inhibitory effect towards steroidogenic enzymes, making it an attractive candidate for CS treatment with a potentially lower toxicity profile than its racemate.2,3,7
Levoketoconazole was approved by the FDA on December 30, 2021, and is currently marketed under the registered trademark RECORLEV by Xeris Pharmaceuticals, Inc.6
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Levoketoconazole (DB05667)
- Weight
- Average: 531.431
Monoisotopic: 530.148760818 - Chemical Formula
- C26H28Cl2N4O4
- Synonyms
- Levoketoconazole
- External IDs
- COR-003
- COR003
- DIO-902
Pharmacology
- Indication
Levoketoconazole is indicated for the treatment of endogenous hypercortisolemia in adult patients with Cushing’s syndrome for whom surgery is not an option or has not been curative. Levoketoconazole is not indicated for the treatment of fungal infections.6
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Symptomatic treatment of Endogenous cushing's syndrome •••••••••••• ••••• ••••••• •• ••• •• •••••• •• ••• ••• •••• •••••••• •••••• - Contraindications & Blackbox Warnings
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Levoketoconazole is a steroidogenic inhibitor that reduces morbidity and mortality due to hypercortisolism associated with Cushing's syndrome.2,6,7 Due to its mechanism of action, levoketoconazole may cause hypocortisolism and decreased serum testosterone levels in both sexes. Levoketoconazole is known to cause dose-dependent increases in the QTc interval; at dose levels between 150 and 600 mg twice daily, the largest mean increase in the QTc was 24 msec. Hypersensitivity to levoketoconazole has been observed, and anaphylaxis has been reported with the racemic ketoconazole.6
- Mechanism of action
Cushing's syndrome (CS) is underpinned by chronic hypercortisolism leading to multisystem morbidity, including effects on the cardiovascular and endocrine systems, metabolic syndrome with accompanying changes in body composition, neuropsychiatric effects, changes in blood pressure and chemistry, and opportunistic infections. CS is most commonly caused by an ACTH-producing pituitary adenoma (ACTH-dependent CS) but may also be caused by an adrenal adenoma, adrenal carcinoma, or adrenal hyperplasia (ACTH-independent CS). As hypercortisolism is associated with significant morbidity and increased mortality, the primary goal of therapy is to normalize cortisol levels, either through surgical resection of the associated tumour or, when surgery is unsuccessful or inappropriate, radiological or chemotherapeutic treatment.1,2
Different medications target different axes of the underlying etiology of CS; steroidogenic enzyme inhibitors are effective against all forms of CS. Ketoconazole, which is indicated for endogenous CS by the EMA and used for the same indication off-label in the US,2 is a racemate of 2S,4R (levoketoconazole) and 2R,4S (dextroketoconazole) cis-enantiomers known to inhibit multiple CYP450 enzymes.2 Studies using enantiomerically pure versions deduced that levoketoconazole is between 1.2-2.7 times more potent at inhibiting the key steroidogenic enzymes CYP11A1, CYP11B1, CYP11B2, and CYP17A1 than racemic ketoconazole, and ~15-25 times more potent than dextroketoconazole, suggesting that the majority of the therapeutic efficacy of ketoconazole in CS is due to levoketoconazole.2,3,7 Hence, levoketoconazole directly inhibits key enzymes in cortisol and testosterone synthesis.6
As levoketoconazole is a more potent steroidogenic inhibitor than ketoconazole, lower concentrations should achieve the same therapeutic effect and may also decrease the risk of hepatic toxicity.2 In addition to the dose consideration, levoketoconazole is 12 times less potent than dextroketoconazole at inhibiting CYP7A1, a rate-limiting enzyme for bile acid synthesis.2,3 However, levoketoconazole is roughly two times more potent at inhibiting CYP3A4 than dextroketoconazole.4,5
Target Actions Organism ASteroid 17-alpha-hydroxylase/17,20 lyase inhibitorHumans ACytochrome P450 11B1, mitochondrial inhibitorHumans ACytochrome P450 11B2, mitochondrial inhibitorHumans ACholesterol side-chain cleavage enzyme, mitochondrial inhibitorHumans NLanosterol 14-alpha demethylase inhibitorHumans - Absorption
Levoketoconazole has a Tmax of ~1.5-2 hours regardless of dose, while the Cmax increases proportionally with the dose. The AUC increases greater than dose proportionally over the recommended range of 150-600 mg. Co-administration of a single 600 mg oral dose with a high-fat meal increased the AUC by 30% with no change in Cmax and a delay in the median Tmax from two to four hours. The pharmacokinetics of racemic ketoconazole are not significantly different in patients with renal impairment; given the extensive hepatic metabolism of ketoconazole, it is expected that hepatic impairment will affect the pharmacokinetics of levoketoconazole.6
- Volume of distribution
Levoketoconazole has an apparent volume of distribution of 31-41 L, approximating total body water.6
- Protein binding
Levoketoconazole is 99.3% bound to human plasma proteins.6
- Metabolism
No in vitro or in vivo studies of levoketoconazole metabolism have been performed. Ketoconazole is known to be hepatically metabolized to several inactive metabolites, mainly through oxidation of the imidazole and piperazine rings, together with oxidative O-dealkylation and aromatic hydroxylation.6 Levoketoconazole is known to both induce and strongly inhibit CYP3A4.4,5,6
- Route of elimination
Approximately 13% of racemic ketoconazole is excreted in the urine, 2-4% as unchanged drug, while the major excretion route is in the feces, accounting for ~57%.6
- Half-life
Levoketoconazole has a plasma elimination half-life of 3-4.5 hours following a single dose and 4-6 hours following multiple doses.6
- Clearance
Not Available
- Adverse Effects
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Toxicity information regarding levoketoconazole is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as nausea, vomiting, hypokalemia, hemorrhage, systemic hypertension, headache, hepatic injury, abnormal uterine bleeding, erythema, fatigue, abdominal pain/dyspepsia, arthritis, upper respiratory infection, myalgia, arrhythmia, back pain, insomnia/sleep disturbances, and peripheral edema. Symptomatic and supportive measures are recommended; within the first hour following ingestion, activated charcoal may be beneficial.6
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your software1,2-Benzodiazepine The metabolism of 1,2-Benzodiazepine can be decreased when combined with Levoketoconazole. Abametapir The serum concentration of Levoketoconazole can be increased when it is combined with Abametapir. Abemaciclib The metabolism of Abemaciclib can be decreased when combined with Levoketoconazole. Abiraterone The metabolism of Abiraterone can be decreased when combined with Levoketoconazole. Acalabrutinib The metabolism of Acalabrutinib can be decreased when combined with Levoketoconazole. - Food Interactions
- Avoid excessive or chronic alcohol consumption. Concomitant alcohol consumption may result in a disulfiram-like reaction characterized by rash, flushing, peripheral edema, nausea, and headache. These symptoms typically subside within hours.
- Take with or without food. In healthy subjects administered a single 600 mg oral dose of levoketoconazole, a high-fat meal increased the AUC by 30% with no change in the maximum plasma concentration but a delay to reach this value of between two and four hours. These changes are not considered clinically significant.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Recorlev Tablet 150 mg/1 Oral Xeris Pharmaceuticals, Inc. 2021-12-30 Not applicable US 
Categories
- ATC Codes
- H02CA04 — Levoketoconazole
- Drug Categories
- Adrenal Cortex Hormones
- Antiadrenal Preparations
- Anticorticosteroids
- Antifungal Agents
- Azole Antifungals
- Corticosteroids
- Corticosteroids for Systemic Use
- Cortisol Synthesis Inhibitors
- Cytochrome P-450 CYP1A2 Inducers
- Cytochrome P-450 CYP1A2 Inducers (strength unknown)
- Cytochrome P-450 CYP2B6 Inhibitors
- Cytochrome P-450 CYP2B6 Inhibitors (strength unknown)
- Cytochrome P-450 CYP2C8 Inhibitors
- Cytochrome P-450 CYP2C8 Inhibitors (strength unknown)
- Cytochrome P-450 CYP3A Inducers
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Inducers
- Cytochrome P-450 CYP3A4 Inducers (strength unknown)
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (strong)
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A5 Inducers
- Cytochrome P-450 CYP3A5 Inducers (strength unknown)
- Cytochrome P-450 CYP3A5 Inhibitors
- Cytochrome P-450 CYP3A5 Inhibitors (strength unknown)
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- MATE 1 Inhibitors
- MATE inhibitors
- OCT2 Inhibitors
- P-glycoprotein inhibitors
- QTc Prolonging Agents
- Systemic Hormonal Preparations, Excl. Sex Hormones and Insulins
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as phenylpiperazines. These are compounds containing a phenylpiperazine skeleton, which consists of a piperazine bound to a phenyl group.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Diazinanes
- Sub Class
- Piperazines
- Direct Parent
- Phenylpiperazines
- Alternative Parents
- N-arylpiperazines / Aminophenyl ethers / Phenoxy compounds / Aniline and substituted anilines / Dialkylarylamines / Dichlorobenzenes / Alkyl aryl ethers / Ketals / Aryl chlorides / N-substituted imidazoles show 12 more
- Substituents
- 1,3-dichlorobenzene / Acetal / Acetamide / Alkyl aryl ether / Amine / Amino acid or derivatives / Aminophenyl ether / Aniline or substituted anilines / Aromatic heteromonocyclic compound / Aryl chloride show 34 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- cis-1-acetyl-4-(4-\{[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy\}phenyl)piperazine (CHEBI:47518)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 2DJ8R0NT7K
- CAS number
- 142128-57-2
- InChI Key
- XMAYWYJOQHXEEK-ZEQKJWHPSA-N
- InChI
- InChI=1S/C26H28Cl2N4O4/c1-19(33)31-10-12-32(13-11-31)21-3-5-22(6-4-21)34-15-23-16-35-26(36-23,17-30-9-8-29-18-30)24-7-2-20(27)14-25(24)28/h2-9,14,18,23H,10-13,15-17H2,1H3/t23-,26-/m1/s1
- IUPAC Name
- 1-[4-(4-{[(2S,4R)-2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)methyl]-1,3-dioxolan-4-yl]methoxy}phenyl)piperazin-1-yl]ethan-1-one
- SMILES
- CC(=O)N1CCN(CC1)C1=CC=C(OC[C@@H]2CO[C@](CN3C=CN=C3)(O2)C2=CC=C(Cl)C=C2Cl)C=C1
References
- Synthesis Reference
Rotstein DM, Kertesz DJ, Walker KA, Swinney DC: Stereoisomers of ketoconazole: preparation and biological activity. J Med Chem. 1992 Jul 24;35(15):2818-25.
- General References
- Feelders RA, Newell-Price J, Pivonello R, Nieman LK, Hofland LJ, Lacroix A: Advances in the medical treatment of Cushing's syndrome. Lancet Diabetes Endocrinol. 2019 Apr;7(4):300-312. doi: 10.1016/S2213-8587(18)30155-4. Epub 2018 Jul 20. [Article]
- Fleseriu M, Auchus RJ, Pivonello R, Salvatori R, Zacharieva S, Biller BMK: Levoketoconazole: a novel treatment for endogenous Cushing's syndrome. Expert Rev Endocrinol Metab. 2021 Jul;16(4):159-174. doi: 10.1080/17446651.2021.1945440. Epub 2021 Aug 12. [Article]
- Rotstein DM, Kertesz DJ, Walker KA, Swinney DC: Stereoisomers of ketoconazole: preparation and biological activity. J Med Chem. 1992 Jul 24;35(15):2818-25. [Article]
- Novotna A, Krasulova K, Bartonkova I, Korhonova M, Bachleda P, Anzenbacher P, Dvorak Z: Dual effects of ketoconazole cis-enantiomers on CYP3A4 in human hepatocytes and HepG2 Cells. PLoS One. 2014 Oct 24;9(10):e111286. doi: 10.1371/journal.pone.0111286. eCollection 2014. [Article]
- Dilmaghanian S, Gerber JG, Filler SG, Sanchez A, Gal J: Enantioselectivity of inhibition of cytochrome P450 3A4 (CYP3A4) by ketoconazole: Testosterone and methadone as substrates. Chirality. 2004 Feb;16(2):79-85. doi: 10.1002/chir.10294. [Article]
- FDA Approved Drug Products: RECORLEV (levoketoconazole) tablets [Link]
- University of Michigan: 2S,4R-Ketoconazole is the Relevant Enantiomer of Ketoconazole for Cortisol Synthesis Inhibition: Steroidogenic P450s Inhibition Involves Multiple Mechanisms [Link]
- External Links
- Human Metabolome Database
- HMDB0012242
- ChemSpider
- 43284
- BindingDB
- 31768
- 2588846
- ChEBI
- 47518
- ChEMBL
- CHEMBL295698
- ZINC
- ZINC000000643153
- PharmGKB
- PA450146
- PDBe Ligand
- KLN
- Wikipedia
- Levoketoconazole
- PDB Entries
- 2jjp / 2v0m
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample data3 Completed Treatment Cushing's Disease / Cushing's Syndrome 1 somestatus stop reason just information to hide 3 Completed Treatment Endogenous Cushing's Syndrome 2 somestatus stop reason just information to hide 2 Terminated Treatment Type 2 Diabetes Mellitus 1 somestatus stop reason just information to hide 2, 3 Terminated Treatment Type 2 Diabetes Mellitus 1 somestatus stop reason just information to hide 1 Completed Other Healthy Volunteers (HV) 3 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral 150 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US10835530 No 2020-11-17 2026-01-10 US US10517868 No 2019-12-31 2026-01-10 US US10098877 No 2018-10-16 2026-01-10 US US9918984 No 2018-03-20 2026-01-10 US US11020393 No 2021-06-01 2040-03-02 US US11278547 No 2020-03-02 2040-03-02 US US11478471 No 2006-01-10 2026-01-10 US US11903940 No 2020-03-02 2040-03-02 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.00931 mg/mL ALOGPS logP 4.3 ALOGPS logP 4.19 Chemaxon logS -4.8 ALOGPS pKa (Strongest Basic) 6.42 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 6 Chemaxon Hydrogen Donor Count 0 Chemaxon Polar Surface Area 69.06 Å2 Chemaxon Rotatable Bond Count 7 Chemaxon Refractivity 138.07 m3·mol-1 Chemaxon Polarizability 54.67 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 1 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 228.6155601 predictedDarkChem Lite v0.1.0 [M-H]- 206.71898 predictedDeepCCS 1.0 (2019) [M+H]+ 229.1934601 predictedDarkChem Lite v0.1.0 [M+H]+ 209.11455 predictedDeepCCS 1.0 (2019) [M+Na]+ 228.9574601 predictedDarkChem Lite v0.1.0 [M+Na]+ 215.02707 predictedDeepCCS 1.0 (2019)
Targets
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- Curator comments
- Levoketoconazole binds CYP17A1 with a binding constant of 110 ± 10 nM and inhibits this enzyme with an IC50 of 28 nM.
- General Function
- A cytochrome P450 monooxygenase involved in corticoid and androgen biosynthesis (PubMed:22266943, PubMed:25301938, PubMed:27339894, PubMed:9452426). Catalyzes 17-alpha hydroxylation of C21 steroids, which is common for both pathways. A second oxidative step, required only for androgen synthesis, involves an acyl-carbon cleavage. The 17-alpha hydroxy intermediates, as part of adrenal glucocorticoids biosynthesis pathway, are precursors of cortisol (Probable) (PubMed:25301938, PubMed:9452426). Hydroxylates steroid hormones, pregnenolone and progesterone to form 17-alpha hydroxy metabolites, followed by the cleavage of the C17-C20 bond to form C19 steroids, dehydroepiandrosterone (DHEA) and androstenedione (PubMed:22266943, PubMed:25301938, PubMed:27339894, PubMed:36640554, PubMed:9452426). Has 16-alpha hydroxylase activity. Catalyzes 16-alpha hydroxylation of 17-alpha hydroxy pregnenolone, followed by the cleavage of the C17-C20 bond to form 16-alpha-hydroxy DHEA (PubMed:36640554). Also 16-alpha hydroxylates androgens, relevant for estriol synthesis (PubMed:25301938, PubMed:27339894). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:22266943, PubMed:25301938, PubMed:27339894, PubMed:9452426)
- Specific Function
- heme binding
- Gene Name
- CYP17A1
- Uniprot ID
- P05093
- Uniprot Name
- Steroid 17-alpha-hydroxylase/17,20 lyase
- Molecular Weight
- 57369.995 Da
References
- Fleseriu M, Auchus RJ, Pivonello R, Salvatori R, Zacharieva S, Biller BMK: Levoketoconazole: a novel treatment for endogenous Cushing's syndrome. Expert Rev Endocrinol Metab. 2021 Jul;16(4):159-174. doi: 10.1080/17446651.2021.1945440. Epub 2021 Aug 12. [Article]
- Rotstein DM, Kertesz DJ, Walker KA, Swinney DC: Stereoisomers of ketoconazole: preparation and biological activity. J Med Chem. 1992 Jul 24;35(15):2818-25. [Article]
- University of Michigan: 2S,4R-Ketoconazole is the Relevant Enantiomer of Ketoconazole for Cortisol Synthesis Inhibition: Steroidogenic P450s Inhibition Involves Multiple Mechanisms [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- Curator comments
- Levoketoconazole binds CYP11B1 with a binding constant of 140 ± 10 nM and inhibits this enzyme with an IC50 of 52 nM.
- General Function
- A cytochrome P450 monooxygenase involved in the biosynthesis of adrenal corticoids (PubMed:12530636, PubMed:1518866, PubMed:1775135, PubMed:18215163, PubMed:23322723). Catalyzes a variety of reactions that are essential for many species, including detoxification, defense, and the formation of endogenous chemicals like steroid hormones. Steroid 11beta, 18- and 19-hydroxylase with preferred regioselectivity at 11beta, then 18, and lastly 19 (By similarity). Catalyzes the hydroxylation of 11-deoxycortisol and 11-deoxycorticosterone (21-hydroxyprogesterone) at 11beta position, yielding cortisol or corticosterone, respectively, but cannot produce aldosterone (PubMed:12530636, PubMed:1518866, PubMed:1775135, PubMed:18215163, PubMed:23322723). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate for hydroxylation and reducing the second into a water molecule. Two electrons are provided by NADPH via a two-protein mitochondrial transfer system comprising flavoprotein FDXR (adrenodoxin/ferredoxin reductase) and nonheme iron-sulfur protein FDX1 or FDX2 (adrenodoxin/ferredoxin) (PubMed:18215163). Due to its lack of 18-oxidation activity, it is incapable of generating aldosterone (PubMed:23322723). Could also be involved in the androgen metabolic pathway (Probable)
- Specific Function
- corticosterone 18-monooxygenase activity
- Gene Name
- CYP11B1
- Uniprot ID
- P15538
- Uniprot Name
- Cytochrome P450 11B1, mitochondrial
- Molecular Weight
- 57572.44 Da
References
- Fleseriu M, Auchus RJ, Pivonello R, Salvatori R, Zacharieva S, Biller BMK: Levoketoconazole: a novel treatment for endogenous Cushing's syndrome. Expert Rev Endocrinol Metab. 2021 Jul;16(4):159-174. doi: 10.1080/17446651.2021.1945440. Epub 2021 Aug 12. [Article]
- Rotstein DM, Kertesz DJ, Walker KA, Swinney DC: Stereoisomers of ketoconazole: preparation and biological activity. J Med Chem. 1992 Jul 24;35(15):2818-25. [Article]
- University of Michigan: 2S,4R-Ketoconazole is the Relevant Enantiomer of Ketoconazole for Cortisol Synthesis Inhibition: Steroidogenic P450s Inhibition Involves Multiple Mechanisms [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- Curator comments
- Levoketoconazole inhibits CYP11B2 with an IC50 of 150 nM.
- General Function
- A cytochrome P450 monooxygenase that catalyzes the biosynthesis of aldosterone, the main mineralocorticoid in the human body responsible for salt and water homeostasis, thus involved in blood pressure regulation, arterial hypertension, and the development of heart failure (PubMed:11856349, PubMed:12530636, PubMed:1518866, PubMed:15356073, PubMed:1594605, PubMed:1775135, PubMed:22446688, PubMed:23322723, PubMed:9814482, PubMed:9814506). Catalyzes three sequential oxidative reactions of 11-deoxycorticosterone (21-hydroxyprogesterone), namely 11-beta hydroxylation, followed by two successive oxidations at C18 yielding 18-hydroxy and then 18-oxo intermediates (that would not leave the enzyme active site during the consecutive hydroxylation reactions), ending with the formation of aldosterone (PubMed:11856349, PubMed:12530636, PubMed:1518866, PubMed:1594605, PubMed:1775135, PubMed:22446688, PubMed:23322723, PubMed:9814506). Can also produce 18-hydroxycortisol and 18-oxocortisol, derived from successive oxidations of cortisol at C18, normally found at very low levels, but significantly increased in primary aldosteronism, the most common form of secondary hypertension (PubMed:15356073, PubMed:9814482). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate and reducing the second into a water molecule. Two electrons are provided by NADPH via a two-protein mitochondrial transfer system comprising flavoprotein FDXR (adrenodoxin/ferredoxin reductase) and nonheme iron-sulfur protein FDX1 or FDX2 (adrenodoxin/ferredoxin) (PubMed:11856349, PubMed:1594605, PubMed:23322723, PubMed:9814506). Could also be involved in the androgen metabolic pathway (Probable)
- Specific Function
- corticosterone 18-monooxygenase activity
- Gene Name
- CYP11B2
- Uniprot ID
- P19099
- Uniprot Name
- Cytochrome P450 11B2, mitochondrial
- Molecular Weight
- 57559.62 Da
References
- Fleseriu M, Auchus RJ, Pivonello R, Salvatori R, Zacharieva S, Biller BMK: Levoketoconazole: a novel treatment for endogenous Cushing's syndrome. Expert Rev Endocrinol Metab. 2021 Jul;16(4):159-174. doi: 10.1080/17446651.2021.1945440. Epub 2021 Aug 12. [Article]
- Rotstein DM, Kertesz DJ, Walker KA, Swinney DC: Stereoisomers of ketoconazole: preparation and biological activity. J Med Chem. 1992 Jul 24;35(15):2818-25. [Article]
- University of Michigan: 2S,4R-Ketoconazole is the Relevant Enantiomer of Ketoconazole for Cortisol Synthesis Inhibition: Steroidogenic P450s Inhibition Involves Multiple Mechanisms [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- Curator comments
- Levoketoconazole binds CYP11A1 with a binding constant of 840 ± 50 nM and inhibits this enzyme with an IC50 of 1450 nM.
- General Function
- A cytochrome P450 monooxygenase that catalyzes the side-chain hydroxylation and cleavage of cholesterol to pregnenolone, the precursor of most steroid hormones (PubMed:21636783). Catalyzes three sequential oxidation reactions of cholesterol, namely the hydroxylation at C22 followed with the hydroxylation at C20 to yield 20R,22R-hydroxycholesterol that is further cleaved between C20 and C22 to yield the C21-steroid pregnenolone and 4-methylpentanal (PubMed:21636783). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate and reducing the second into a water molecule. Two electrons are provided by NADPH via a two-protein mitochondrial transfer system comprising flavoprotein FDXR (adrenodoxin/ferredoxin reductase) and nonheme iron-sulfur protein FDX1 or FDX2 (adrenodoxin/ferredoxin) (PubMed:21636783)
- Specific Function
- cholesterol monooxygenase (side-chain-cleaving) activity
- Gene Name
- CYP11A1
- Uniprot ID
- P05108
- Uniprot Name
- Cholesterol side-chain cleavage enzyme, mitochondrial
- Molecular Weight
- 60101.87 Da
References
- Fleseriu M, Auchus RJ, Pivonello R, Salvatori R, Zacharieva S, Biller BMK: Levoketoconazole: a novel treatment for endogenous Cushing's syndrome. Expert Rev Endocrinol Metab. 2021 Jul;16(4):159-174. doi: 10.1080/17446651.2021.1945440. Epub 2021 Aug 12. [Article]
- Rotstein DM, Kertesz DJ, Walker KA, Swinney DC: Stereoisomers of ketoconazole: preparation and biological activity. J Med Chem. 1992 Jul 24;35(15):2818-25. [Article]
- University of Michigan: 2S,4R-Ketoconazole is the Relevant Enantiomer of Ketoconazole for Cortisol Synthesis Inhibition: Steroidogenic P450s Inhibition Involves Multiple Mechanisms [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- Curator comments
- Levoketoconazole inhibits CYP51A1 with an IC50 of 47 ± 3 nM, roughly 2.5-times more potent than dextroketoconazole. Levoketoconazole is not indicated for the treatment of fungal infections.
- General Function
- Sterol 14alpha-demethylase that plays a critical role in the cholesterol biosynthesis pathway, being cholesterol the major sterol component in mammalian membranes as well as a precursor for bile acid and steroid hormone synthesis (PubMed:20149798, PubMed:8619637, PubMed:9559662). Cytochrome P450 monooxygenase that catalyzes the three-step oxidative removal of the 14alpha-methyl group (C-32) of sterols such as lanosterol (lanosta-8,24-dien-3beta-ol) and 24,25-dihydrolanosterol (DHL) in the form of formate, and converts the sterols to 4,4-dimethyl-5alpha-cholesta-8,14,24-trien-3beta-ol and 4,4-dimethyl-8,14-cholestadien-3beta-ol, respectively, which are intermediates of cholesterol biosynthesis (PubMed:20149798, PubMed:8619637, PubMed:9559662). Can also demethylate substrates not intrinsic to mammals, such as eburicol (24-methylene-24,25-dihydrolanosterol), but at a lower rate than DHL (PubMed:9559662)
- Specific Function
- heme binding
- Gene Name
- CYP51A1
- Uniprot ID
- Q16850
- Uniprot Name
- Lanosterol 14-alpha demethylase
- Molecular Weight
- 57277.81 Da
References
- Fleseriu M, Auchus RJ, Pivonello R, Salvatori R, Zacharieva S, Biller BMK: Levoketoconazole: a novel treatment for endogenous Cushing's syndrome. Expert Rev Endocrinol Metab. 2021 Jul;16(4):159-174. doi: 10.1080/17446651.2021.1945440. Epub 2021 Aug 12. [Article]
- Rotstein DM, Kertesz DJ, Walker KA, Swinney DC: Stereoisomers of ketoconazole: preparation and biological activity. J Med Chem. 1992 Jul 24;35(15):2818-25. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitorInducer
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
- Specific Function
- 1,8-cineole 2-exo-monooxygenase activity
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Fleseriu M, Castinetti F: Updates on the role of adrenal steroidogenesis inhibitors in Cushing's syndrome: a focus on novel therapies. Pituitary. 2016 Dec;19(6):643-653. doi: 10.1007/s11102-016-0742-1. [Article]
- Novotna A, Krasulova K, Bartonkova I, Korhonova M, Bachleda P, Anzenbacher P, Dvorak Z: Dual effects of ketoconazole cis-enantiomers on CYP3A4 in human hepatocytes and HepG2 Cells. PLoS One. 2014 Oct 24;9(10):e111286. doi: 10.1371/journal.pone.0111286. eCollection 2014. [Article]
- Dilmaghanian S, Gerber JG, Filler SG, Sanchez A, Gal J: Enantioselectivity of inhibition of cytochrome P450 3A4 (CYP3A4) by ketoconazole: Testosterone and methadone as substrates. Chirality. 2004 Feb;16(2):79-85. doi: 10.1002/chir.10294. [Article]
- FDA Approved Drug Products: RECORLEV (levoketoconazole) tablets [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- Curator comments
- Levoketoconazole inhibits CYP2B6 in vitro; use with drugs that are CYP2B6 substrates may result in a drug interaction.
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of endocannabinoids and steroids (PubMed:12865317, PubMed:21289075). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the epoxidation of double bonds of arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:21289075). Hydroxylates steroid hormones, including testosterone at C-16 and estrogens at C-2 (PubMed:12865317, PubMed:21289075). Plays a role in the oxidative metabolism of xenobiotics, including plant lipids and drugs (PubMed:11695850, PubMed:22909231). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850)
- Specific Function
- anandamide 11,12 epoxidase activity
- Gene Name
- CYP2B6
- Uniprot ID
- P20813
- Uniprot Name
- Cytochrome P450 2B6
- Molecular Weight
- 56277.81 Da
References
- FDA Approved Drug Products: RECORLEV (levoketoconazole) tablets [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- Curator comments
- Levoketoconazole inhibits CYP2C8 in vitro; use with drugs that are CYP2C8 substrates may result in a drug interaction.
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:15766564, PubMed:19965576, PubMed:7574697). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316)
- Specific Function
- arachidonic acid epoxygenase activity
- Gene Name
- CYP2C8
- Uniprot ID
- P10632
- Uniprot Name
- Cytochrome P450 2C8
- Molecular Weight
- 55824.275 Da
References
- FDA Approved Drug Products: RECORLEV (levoketoconazole) tablets [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inducer
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:11555828, PubMed:12865317). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2 (PubMed:11555828, PubMed:12865317). Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). May act as a major enzyme for all-trans retinoic acid biosynthesis in the liver. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). Primarily catalyzes stereoselective epoxidation of the last double bond of polyunsaturated fatty acids (PUFA), displaying a strong preference for the (R,S) stereoisomer (PubMed:19965576). Catalyzes bisallylic hydroxylation and omega-1 hydroxylation of PUFA (PubMed:9435160). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195). Plays a role in the oxidative metabolism of xenobiotics. Catalyzes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin (PubMed:14725854). Metabolizes caffeine via N3-demethylation (Probable)
- Specific Function
- aromatase activity
- Gene Name
- CYP1A2
- Uniprot ID
- P05177
- Uniprot Name
- Cytochrome P450 1A2
- Molecular Weight
- 58406.915 Da
References
- FDA Approved Drug Products: RECORLEV (levoketoconazole) tablets [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- InhibitorInducer
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of steroid hormones and vitamins (PubMed:10681376, PubMed:11093772, PubMed:12865317, PubMed:2732228). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:10681376, PubMed:11093772, PubMed:12865317, PubMed:2732228). Exhibits high catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes 6beta-hydroxylation of the steroid hormones testosterone, progesterone, and androstenedione (PubMed:2732228). Catalyzes the oxidative conversion of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Also involved in the oxidative metabolism of xenobiotics, including calcium channel blocking drug nifedipine and immunosuppressive drug cyclosporine (PubMed:2732228)
- Specific Function
- aromatase activity
- Gene Name
- CYP3A5
- Uniprot ID
- P20815
- Uniprot Name
- Cytochrome P450 3A5
- Molecular Weight
- 57108.065 Da
References
- Fleseriu M, Castinetti F: Updates on the role of adrenal steroidogenesis inhibitors in Cushing's syndrome: a focus on novel therapies. Pituitary. 2016 Dec;19(6):643-653. doi: 10.1007/s11102-016-0742-1. [Article]
- Novotna A, Krasulova K, Bartonkova I, Korhonova M, Bachleda P, Anzenbacher P, Dvorak Z: Dual effects of ketoconazole cis-enantiomers on CYP3A4 in human hepatocytes and HepG2 Cells. PLoS One. 2014 Oct 24;9(10):e111286. doi: 10.1371/journal.pone.0111286. eCollection 2014. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of endogenous cholesterol and its oxygenated derivatives (oxysterols) (PubMed:11013305, PubMed:12077124, PubMed:19965590, PubMed:21813643, PubMed:2384150). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:11013305, PubMed:12077124, PubMed:19965590, PubMed:21813643, PubMed:2384150). Functions as a critical regulatory enzyme of bile acid biosynthesis and cholesterol homeostasis. Catalyzes the hydroxylation of carbon hydrogen bond at 7-alpha position of cholesterol, a rate-limiting step in cholesterol catabolism and bile acid biosynthesis (PubMed:12077124, PubMed:19965590, PubMed:2384150). 7-alpha hydroxylates several oxysterols, including 4beta-hydroxycholesterol and 24-hydroxycholesterol (PubMed:11013305, PubMed:12077124). Catalyzes the oxidation of the 7,8 double bond of 7-dehydrocholesterol and lathosterol with direct and predominant formation of the 7-keto derivatives (PubMed:21813643)
- Specific Function
- 24-hydroxycholesterol 7alpha-hydroxylase activity
- Gene Name
- CYP7A1
- Uniprot ID
- P22680
- Uniprot Name
- Cytochrome P450 7A1
- Molecular Weight
- 57660.155 Da
References
- Rotstein DM, Kertesz DJ, Walker KA, Swinney DC: Stereoisomers of ketoconazole: preparation and biological activity. J Med Chem. 1992 Jul 24;35(15):2818-25. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- A cytochrome P450 monooxygenase that catalyzes the conversion of C19 androgens, androst-4-ene-3,17-dione (androstenedione) and testosterone to the C18 estrogens, estrone and estradiol, respectively (PubMed:27702664, PubMed:2848247). Catalyzes three successive oxidations of C19 androgens: two conventional oxidations at C19 yielding 19-hydroxy and 19-oxo/19-aldehyde derivatives, followed by a third oxidative aromatization step that involves C1-beta hydrogen abstraction combined with cleavage of the C10-C19 bond to yield a phenolic A ring and formic acid (PubMed:20385561). Alternatively, the third oxidative reaction yields a 19-norsteroid and formic acid. Converts dihydrotestosterone to delta1,10-dehydro 19-nordihydrotestosterone and may play a role in homeostasis of this potent androgen (PubMed:22773874). Also displays 2-hydroxylase activity toward estrone (PubMed:22773874). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:20385561, PubMed:22773874)
- Specific Function
- aromatase activity
- Gene Name
- CYP19A1
- Uniprot ID
- P11511
- Uniprot Name
- Aromatase
- Molecular Weight
- 57882.48 Da
References
- Rotstein DM, Kertesz DJ, Walker KA, Swinney DC: Stereoisomers of ketoconazole: preparation and biological activity. J Med Chem. 1992 Jul 24;35(15):2818-25. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- A cytochrome P450 monooxygenase that plays a major role in adrenal steroidogenesis. Catalyzes the hydroxylation at C-21 of progesterone and 17alpha-hydroxyprogesterone to respectively form 11-deoxycorticosterone and 11-deoxycortisol, intermediate metabolites in the biosynthetic pathway of mineralocorticoids and glucocorticoids (PubMed:10602386, PubMed:16984992, PubMed:22014889, PubMed:25855791, PubMed:27721825). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:25855791)
- Specific Function
- 17-hydroxyprogesterone 21-hydroxylase activity
- Gene Name
- CYP21A2
- Uniprot ID
- P08686
- Uniprot Name
- Steroid 21-hydroxylase
- Molecular Weight
- 56000.94 Da
References
- Fleseriu M, Castinetti F: Updates on the role of adrenal steroidogenesis inhibitors in Cushing's syndrome: a focus on novel therapies. Pituitary. 2016 Dec;19(6):643-653. doi: 10.1007/s11102-016-0742-1. [Article]
- Rotstein DM, Kertesz DJ, Walker KA, Swinney DC: Stereoisomers of ketoconazole: preparation and biological activity. J Med Chem. 1992 Jul 24;35(15):2818-25. [Article]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- ATP-dependent translocase ABCB1
- Molecular Weight
- 141477.255 Da
References
- FDA Approved Drug Products: RECORLEV (levoketoconazole) tablets [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Multidrug efflux pump that functions as a H(+)/organic cation antiporter (PubMed:16330770, PubMed:17509534). Plays a physiological role in the excretion of cationic compounds including endogenous metabolites, drugs, toxins through the kidney and liver, into urine and bile respectively (PubMed:16330770, PubMed:17495125, PubMed:17509534, PubMed:17582384, PubMed:18305230, PubMed:19158817, PubMed:21128598, PubMed:24961373). Mediates the efflux of endogenous compounds such as creatinine, vitamin B1/thiamine, agmatine and estrone-3-sulfate (PubMed:16330770, PubMed:17495125, PubMed:17509534, PubMed:17582384, PubMed:18305230, PubMed:19158817, PubMed:21128598, PubMed:24961373). May also contribute to regulate the transport of cationic compounds in testis across the blood-testis-barrier (Probable)
- Specific Function
- antiporter activity
- Gene Name
- SLC47A1
- Uniprot ID
- Q96FL8
- Uniprot Name
- Multidrug and toxin extrusion protein 1
- Molecular Weight
- 61921.585 Da
References
- FDA Approved Drug Products: RECORLEV (levoketoconazole) tablets [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Electrogenic voltage-dependent transporter that mediates the transport of a variety of organic cations such as endogenous bioactive amines, cationic drugs and xenobiotics (PubMed:9260930, PubMed:9687576). Functions as a Na(+)-independent, bidirectional uniporter (PubMed:21128598, PubMed:9687576). Cation cellular uptake or release is driven by the electrochemical potential, i.e. membrane potential and concentration gradient (PubMed:15212162, PubMed:9260930, PubMed:9687576). However, may also engage electroneutral cation exchange when saturating concentrations of cation substrates are reached (By similarity). Predominantly expressed at the basolateral membrane of hepatocytes and proximal tubules and involved in the uptake and disposition of cationic compounds by hepatic and renal clearance from the blood flow (PubMed:15783073). Implicated in monoamine neurotransmitters uptake such as histamine, dopamine, adrenaline/epinephrine, noradrenaline/norepinephrine, serotonin and tyramine, thereby supporting a physiological role in the central nervous system by regulating interstitial concentrations of neurotransmitters (PubMed:16581093, PubMed:17460754, PubMed:9687576). Also capable of transporting dopaminergic neuromodulators cyclo(his-pro), salsolinol and N-methyl-salsolinol, thereby involved in the maintenance of dopaminergic cell integrity in the central nervous system (PubMed:17460754). Mediates the bidirectional transport of acetylcholine (ACh) at the apical membrane of ciliated cell in airway epithelium, thereby playing a role in luminal release of ACh from bronchial epithelium (PubMed:15817714). Also transports guanidine and endogenous monoamines such as vitamin B1/thiamine, creatinine and N-1-methylnicotinamide (NMN) (PubMed:12089365, PubMed:15212162, PubMed:17072098, PubMed:24961373, PubMed:9260930). Mediates the uptake and efflux of quaternary ammonium compound choline (PubMed:9260930). Mediates the bidirectional transport of polyamine agmatine and the uptake of polyamines putrescine and spermidine (PubMed:12538837, PubMed:21128598). Able to transport non-amine endogenous compounds such as prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) (PubMed:11907186). Also involved in the uptake of xenobiotic 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP) (PubMed:12395288, PubMed:16394027). May contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable)
- Specific Function
- acetylcholine transmembrane transporter activity
- Gene Name
- SLC22A2
- Uniprot ID
- O15244
- Uniprot Name
- Solute carrier family 22 member 2
- Molecular Weight
- 62579.99 Da
References
- FDA Approved Drug Products: RECORLEV (levoketoconazole) tablets [Link]
Drug created at November 18, 2007 18:26 / Updated at September 26, 2022 19:02