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 Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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 (strength unknown)
- 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 Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 3 Completed Treatment Cushing's Disease / Cushing's Syndrome 1 3 Completed Treatment Endogenous Cushing's Syndrome 2 2 Terminated Treatment Type 2 Diabetes Mellitus 1 2, 3 Terminated Treatment Type 2 Diabetes Mellitus 1 1 Completed Other Healthy Subjects (HS) 3
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
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
- 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
- Steroid 17-alpha-monooxygenase activity
- Specific Function
- Conversion of pregnenolone and progesterone to their 17-alpha-hydroxylated products and subsequently to dehydroepiandrosterone (DHEA) and androstenedione. Catalyzes both the 17-alpha-hydroxylation ...
- 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
- Steroid 11-beta-monooxygenase activity
- Specific Function
- Has steroid 11-beta-hydroxylase activity. In addition to this activity, the 18 or 19-hydroxylation of steroids and the aromatization of androstendione to estrone have also been ascribed to cytochro...
- 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
- Steroid 11-beta-monooxygenase activity
- Specific Function
- Preferentially catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone.
- 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
- Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, nad(p)h as one donor, and incorporation of one atom of oxygen
- Specific Function
- Catalyzes the side-chain cleavage reaction of cholesterol to pregnenolone.
- 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 14-demethylase activity
- Specific Function
- Catalyzes C14-demethylation of lanosterol; it transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol.
- Gene Name
- CYP51A1
- Uniprot ID
- Q16850
- Uniprot Name
- Lanosterol 14-alpha demethylase
- Molecular Weight
- 56805.26 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
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- 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
- Steroid hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- 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
- Steroid hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- 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
- Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP1A2
- Uniprot ID
- P05177
- Uniprot Name
- Cytochrome P450 1A2
- Molecular Weight
- 58293.76 Da
References
- FDA Approved Drug Products: RECORLEV (levoketoconazole) tablets [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- InhibitorInducer
- General Function
- Oxygen binding
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- 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:2384150, PubMed:21813643). 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:2384150, PubMed:11013305, PubMed:12077124, PubMed:19965590, PubMed:21813643). 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
- Oxygen binding
- Specific Function
- Catalyzes the formation of aromatic C18 estrogens from C19 androgens.
- 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
- Steroid hydroxylase activity
- Specific Function
- Specifically catalyzes the 21-hydroxylation of steroids. Required for the adrenal synthesis of mineralocorticoids and glucocorticoids.
- Gene Name
- CYP21A2
- Uniprot ID
- P08686
- Uniprot Name
- Steroid 21-hydroxylase
- Molecular Weight
- 55886.805 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
- Xenobiotic-transporting atpase activity
- Specific Function
- Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- Multidrug resistance protein 1
- 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
- Monovalent cation:proton antiporter activity
- Specific Function
- Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
- 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
- Quaternary ammonium group transmembrane transporter activity
- Specific Function
- Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creat...
- 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