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
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

Reduce drug development failure rates
Build, train, & validate machine-learning models
with evidence-based and structured datasets.
See how
Build, train, & validate predictive machine-learning models with structured datasets.
See how
Associated Conditions
Contraindications & Blackbox Warnings
Avoid life-threatening adverse drug events
Improve clinical decision support with information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.
Learn more
Avoid life-threatening adverse drug events & improve clinical decision support.
Learn more
Pharmacodynamics

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

TargetActionsOrganism
ASteroid 17-alpha-hydroxylase/17,20 lyase
inhibitor
Humans
ACytochrome P450 11B1, mitochondrial
inhibitor
Humans
ACytochrome P450 11B2, mitochondrial
inhibitor
Humans
ACholesterol side-chain cleavage enzyme, mitochondrial
inhibitor
Humans
NLanosterol 14-alpha demethylase
inhibitor
Humans
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
Improve decision support & research outcomes
With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.
Learn more
Improve decision support & research outcomes with our structured adverse effects data.
Learn more
Toxicity

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.
DrugInteraction
1,2-BenzodiazepineThe metabolism of 1,2-Benzodiazepine can be decreased when combined with Levoketoconazole.
AbametapirThe serum concentration of Levoketoconazole can be increased when it is combined with Abametapir.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Levoketoconazole.
AbirateroneThe metabolism of Abiraterone can be decreased when combined with Levoketoconazole.
AcalabrutinibThe metabolism of Acalabrutinib can be decreased when combined with Levoketoconazole.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Levoketoconazole.
AcetaminophenThe metabolism of Acetaminophen can be decreased when combined with Levoketoconazole.
AcyclovirThe excretion of Acyclovir can be decreased when combined with Levoketoconazole.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Levoketoconazole.
AlbendazoleThe metabolism of Albendazole can be decreased when combined with Levoketoconazole.
Identify potential medication risks
Easily compare up to 40 drugs with our drug interaction checker.
Get severity rating, description, and management advice.
Learn more
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 regions
Our datasets provide approved product information including:
dosage, form, labeller, route of administration, and marketing period.
Access now
Access drug product information from over 10 global regions.
Access now
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
RecorlevTablet150 mg/1OralXeris Pharmaceuticals, Inc.2021-12-30Not applicableUS flag

Categories

Drug Categories
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
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. FDA Approved Drug Products: RECORLEV (levoketoconazole) tablets [Link]
  7. University of Michigan: 2S,4R-Ketoconazole is the Relevant Enantiomer of Ketoconazole for Cortisol Synthesis Inhibition: Steroidogenic P450s Inhibition Involves Multiple Mechanisms [Link]
Human Metabolome Database
HMDB0012242
ChemSpider
43284
BindingDB
31768
RxNav
2588846
ChEBI
47518
ChEMBL
CHEMBL295698
ZINC
ZINC000000643153
PharmGKB
PA450146
PDBe Ligand
KLN
Wikipedia
Levoketoconazole
PDB Entries
2jjp / 2v0m

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentCushing's Disease / Cushing's Syndrome1
3CompletedTreatmentEndogenous Cushing's Syndrome2
2TerminatedTreatmentType 2 Diabetes Mellitus1
2, 3TerminatedTreatmentType 2 Diabetes Mellitus1
1CompletedOtherHealthy Subjects (HS)3
1, 2CompletedTreatmentType 2 Diabetes Mellitus1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral150 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US10835530No2020-11-172026-01-10US flag
US10517868No2019-12-312026-01-10US flag
US10098877No2018-10-162026-01-10US flag
US9918984No2018-03-202026-01-10US flag
US11020393No2021-06-012040-03-02US flag
US11278547No2020-03-022040-03-02US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00931 mg/mLALOGPS
logP4.3ALOGPS
logP4.19Chemaxon
logS-4.8ALOGPS
pKa (Strongest Basic)6.42Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area69.06 Å2Chemaxon
Rotatable Bond Count7Chemaxon
Refractivity138.07 m3·mol-1Chemaxon
Polarizability54.67 Å3Chemaxon
Number of Rings5Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-001i-3530190000-a2b05a2498270bcd4a7e

Targets

Build, predict & validate machine-learning models
Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
Learn more
Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.
Learn more
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
  1. 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]
  2. 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]
  3. 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
  1. 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]
  2. 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]
  3. 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
  1. 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]
  2. 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]
  3. 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
  1. 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]
  2. 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]
  3. 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
  1. 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]
  2. 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
Substrate
Inhibitor
Inducer
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
  1. 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]
  2. 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]
  3. 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]
  4. 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
  1. 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
  1. 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
  1. FDA Approved Drug Products: RECORLEV (levoketoconazole) tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Inducer
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
  1. 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]
  2. 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
  1. 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
  1. 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
  1. 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]
  2. 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
  1. 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
  1. 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
  1. FDA Approved Drug Products: RECORLEV (levoketoconazole) tablets [Link]

Drug created at November 18, 2007 18:26 / Updated at September 26, 2022 19:02