Isavuconazole
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Identification
- Brand Names
- Cresemba
- Generic Name
- Isavuconazole
- DrugBank Accession Number
- DB11633
- Background
Isavuconazole is an triazole antifungal with broad spectrum of activity and good safety profile 1. It is approved by the FDA and EMA for the treatment of invasive aspergillosis and mucormycosis. It works by inhibiting fungal cell membrane synthesis. Invasive fungal infections pose significant clinical challenges for patients, especially those who are immunocompromised. In vitro, most of the Candida species, most Aspergillus species, Mucorales, Cryptococcus spp., Fusarium species, dermatophytes and dimorphic fungi displayed susceptibility to isavuconzaole 3. Resistance to isavuconazole has been associated with the mutation in the target gene CYP51 Label. Cross-resistance between isavuconazole and other azoles was also proposed although the clinical relevance is unclear Label.
As isavuconazole displays low water solubility, it is found as an active ingredient of its prodrug, Isavuconazonium. The prodrug formulation of isavuconazole is FDA- and EMA-approved and is marketed under the trade name Cresemba for the treatment of invasive aspergillosis and mucormycosis as oral or intravenous administration. The intravenous formulation is cyclodextrin-free which gives isavuconazole an advantage over other azole antifungals that requires cyclodextrin for facilitating drug solubility; this is because cyclodextrin has a potential for nephrotoxicity 3. It is proposed that the intravenous and oral dosing can be used interchangeably 4, without the need for a repeat loading dose when transitioning from an IV to an oral formulation 1. Isavuconazonium displays excellent water solubility for intravenous formulations, good absorption, and enhanced oral bioavailability 1. Following administration, isavuconazonium undergoes biotransformation to form the active moiety, isavuconazole, for the antifungal actions.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 437.47
Monoisotopic: 437.112187687 - Chemical Formula
- C22H17F2N5OS
- Synonyms
- isavuconazol
- Isavuconazole
- isavuconazolum
- External IDs
- BAL 4815
- BAL-4815
Pharmacology
- Indication
- Indicated for patients 18 years of age and older for the treatment of invasive aspergillosis Label.
- Indicated for patients 18 years of age and older for the treatment of invasive mucormycosis Label, including patients where treatment amphotericin B is inappropriate 4.
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- Pharmacodynamics
Isavucoanzole exhibits antifungal activity against most strains of Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, and Mucorales such as Rhizopus oryzae and Mucormycetes species in vivo and in vitro Label. In a cardiac electrophysiology study involving healthy subjects, isavuconazole induced dose-related shortening of the QTc interval but the additive effect of isavuconazole with other QTc-prolonging drug is unknown Label.
- Mechanism of action
Isavuconazole displays fungicidal actions by disrupting the biosynthesis of ergosterol, which is a key component of fungal cell membrane. It inhibits cytochrome P-450 dependent enzyme lanosterol 14-alpha-demethylase that mediates the conversion of lanosterol to ergosterol. The side arm of of the active isavuconazole molecule allows for greater affinity for the binding pocket in the fungal CYP51 protein by orienting the triazole ring of the molecule to engage with the heme moiety at the bottom of the binding pocket 1,3. This explains the wide antifungal spectrum of isavuconazole and possible cross-resistance to other triazoles 1,3. As a result of lanosterol 14-alpha-demethylase inhibition, toxic methylated sterol precursors such as 14-α-methylated lanosterol, 4,14-dimethylzymosterol, and 24-methylenedihydrolanosterol alter the function of fungal membrane and accumulate within the fungal cytoplasm 3. Depletion of ergosterol within the fungal cell membrane leads to decreased structural integrity and function of the cell membrane, inhibited fungal cell growth and replication 1, and ultimately cell death. Mammalian cell demethylation is less sensitive to isavuconazole inhibition Label.
Mechanism of resistance and reduced susceptibility to isavuconazole arises from mutations in the fungal cyp51A and cyp51B genes coding for the target protein lanosterol 14-alpha-demethylase 4. Other multiple mechanisms leading to resistance, including changes in sterol profile and elevated efflux pump activity of fungal species, cannot be excluded Label.
Target Actions Organism ALanosterol 14-alpha demethylase inhibitorNVoltage-gated inwardly rectifying potassium channel KCNH2 inhibitorHumans NVoltage-dependent L-type calcium channel subunit alpha-1C inhibitorHumans NG protein-activated inward rectifier potassium channel 2 inhibitorHumans NG protein-activated inward rectifier potassium channel 3 inhibitorHumans NATP-sensitive inward rectifier potassium channel 11 inhibitorHumans NPotassium voltage-gated channel subfamily A member 5 inhibitorHumans NA-type voltage-gated potassium channel KCND3 inhibitorHumans NPotassium voltage-gated channel subfamily KQT member 1 inhibitorHumans NSodium channel protein type 5 subunit alpha inhibitorHumans - Absorption
Following oral administration of 200 mg isavuconazole, the mean peak plasma concentration (Cmax) at steady state was 7499 ng/mL. Cmax following oral administration of 600 mg isavuconazole was 20028 ng/mL Label. It is proposed that the Cmax at steady state is reached approximately 2–3 hours after single and multiple dosing of isavuconazole Label. Administration of 400 mg of oral and intravenous isavuconazole resulted in mean AUC of 189462.8 hng/mL and 193906.8 hng/mL, respectively 4. While isavuconazole can be administered with or without food, concurrent consumption of a high-fat meal reduced oral isavuconazole Cmax by 9% and increased AUC by 9% Label. The absolute bioavailability of isavuconazole following oral administration of a single dose of isavuconazole is 98% Label.
- Volume of distribution
The mean steady state volume of distribution (Vss) was approximately 450 L following intravenous administration Label.
- Protein binding
Isavuconazole is highly protein bound (greater than 99%), predominantly to albumin Label.
- Metabolism
Following rapid conversion of the prodrug isavuconazonium to isavuconazole via esterase-mediated hydrolysis, a number of minor metabolites were identified in addition to the active moiety itself and the inactive cleavage product of isavuconazonium. However, no individual metabolite was observed with an AUC greater than 10% of total radio-labeled material Label. The main enzymes involved in the metabolism of isavuconazole are CYP3A4, CYP3A5, and subsequently uridine diphosphate- glucuronosyltransferases (UGT) according to the findings of in vivo and in vitro studies Label.
- Route of elimination
Following oral administration, 46.1% of total radiolabelled isavuconzaole was detected in the feces, and about 45.5% was recovered in urine Label. Unchanged isavuconazole in the urine was less than 1% of the total dose administered Label.
- Half-life
Based on a population pharmacokinetics analysis of healthy subjects and patients, the mean plasma half-life of isavuconazole was 130 hours Label. The mean half life following oral and intravenous administration of 400 mg isavuconazole was 110 and 115 hours, respectively 4.
- Clearance
The clearance (CL) rate was 2.5 ± 1.6 L/h in patients receiving 200 mg isavuconazole orally or intravenously 2.
- Adverse Effects
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- Toxicity
At three times the recommended maintenance dose of isavuconazole, treatment-emergent adverse reactions included headache, dizziness, paresthesia, somnolence, disturbance in attention, dysgeusia, dry mouth, diarrhea, oral hypoesthesia, vomiting, hot flush, anxiety, restlessness, palpitations, tachycardia, photophobia and arthralgia. As there is no specific antidote or effective method of hemodialysis for isavuconazole, supportive treatment with appropriate monitoring is recommended in case of overdose Label.
No mutagenic or clastogenic effects were detected in the in vitro bacterial reverse mutation assay and the in vivo bone marrow micronucleus assay in rats Label. However, isavuconazole was weakly clastogenic at cytotoxic concentrations in the L5178Y tk+/- mouse lymphoma chromosome aberration assay without any significant evidence of increased frequency of micronuclei in an in vivo rat micronucleus test 4. While carcinogenicity studies isavuconazole have not been performed, other drugs in the azole class at near human recommended doses were associated with the development of hepatocellular adenomas and carcinomas in mice and rat carcinogenicity studies Label. At doses up to 90 mg/kg/day, oral isavuconazole did not affect the fertility in male or female rats. Isavuconazole at systemic exposures of subtherapeutic levels was associated with dose-related increases in the incidence of skeletal anomalies in rat and rabbit offsprings 4. In rats, a dose-related increase in the incidence of zygomatic arch fusion was also noted in offspring 4.
- 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 Isavuconazole. Abametapir The serum concentration of Isavuconazole can be increased when it is combined with Abametapir. Abatacept The metabolism of Isavuconazole can be increased when combined with Abatacept. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Isavuconazole. Abiraterone The metabolism of Isavuconazole can be decreased when combined with Abiraterone. - Food Interactions
- Avoid St. John's Wort.
- Exercise caution with grapefruit products.
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 Cresemba Capsule 40 mg Oral Basilea Pharmaceutica Deutschland Gmb H 2024-09-18 Not applicable EU Cresemba Capsule 100 mg Oral Basilea Pharmaceutica Deutschland Gmb H 2020-12-22 Not applicable EU Cresemba Injection, powder, for solution 200 mg Intravenous Basilea Pharmaceutica Deutschland Gmb H 2020-12-22 Not applicable EU
Categories
- ATC Codes
- J02AC05 — Isavuconazole
- Drug Categories
- Anti-Infective Agents
- Antifungal Agents
- Antiinfectives for Systemic Use
- Antimycotics for Systemic Use
- Azole Antifungals
- BCRP/ABCG2 Inhibitors
- Cytochrome P-450 CYP2B6 Inducers
- Cytochrome P-450 CYP2B6 Inducers (weak)
- Cytochrome P-450 CYP2C19 Inhibitors
- Cytochrome P-450 CYP2C19 inhibitors (strength unknown)
- Cytochrome P-450 CYP2C8 Inducers
- Cytochrome P-450 CYP2C8 Inducers (weak)
- Cytochrome P-450 CYP2C8 Inhibitors
- Cytochrome P-450 CYP2C8 Inhibitors (strength unknown)
- Cytochrome P-450 CYP2C9 Inducers
- Cytochrome P-450 CYP2C9 Inducers (weak)
- Cytochrome P-450 CYP2C9 Inhibitors
- Cytochrome P-450 CYP2C9 Inhibitors (strength unknown)
- Cytochrome P-450 CYP2D6 Inhibitors
- Cytochrome P-450 CYP2D6 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 (weak)
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (moderate)
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates (strength unknown)
- Cytochrome P-450 CYP3A5 Inhibitors
- Cytochrome P-450 CYP3A5 Inhibitors (moderate)
- Cytochrome P-450 CYP3A5 Substrates
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Isavuconazole and Prodrugs
- OCT2 Inhibitors
- P-glycoprotein inhibitors
- Triazole and tetrazole derivatives
- Triazole Derivatives
- UGT1A9 Inhibitors
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as phenylpropanes. These are organic compounds containing a phenylpropane moiety.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Phenylpropanes
- Direct Parent
- Phenylpropanes
- Alternative Parents
- Benzonitriles / Fluorobenzenes / 2,4-disubstituted thiazoles / Aryl fluorides / Triazoles / Tertiary alcohols / Heteroaromatic compounds / Nitriles / Azacyclic compounds / Organopnictogen compounds show 3 more
- Substituents
- 1,2,4-triazole / 2,4-disubstituted 1,3-thiazole / Alcohol / Aromatic alcohol / Aromatic heteromonocyclic compound / Aryl fluoride / Aryl halide / Azacycle / Azole / Benzonitrile show 17 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- tertiary alcohol, triazole antifungal drug, conazole antifungal drug, 1,3-thiazole, nitrile, difluorobenzene (CHEBI:85979)
- Affected organisms
- Aspergillis, Candida and other fungi
Chemical Identifiers
- UNII
- 60UTO373KE
- CAS number
- 241479-67-4
- InChI Key
- DDFOUSQFMYRUQK-RCDICMHDSA-N
- InChI
- InChI=1S/C22H17F2N5OS/c1-14(21-28-20(10-31-21)16-4-2-15(9-25)3-5-16)22(30,11-29-13-26-12-27-29)18-8-17(23)6-7-19(18)24/h2-8,10,12-14,30H,11H2,1H3/t14-,22+/m0/s1
- IUPAC Name
- 4-{2-[(2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl]-1,3-thiazol-4-yl}benzonitrile
- SMILES
- C[C@@H](C1=NC(=CS1)C1=CC=C(C=C1)C#N)[C@](O)(CN1C=NC=N1)C1=C(F)C=CC(F)=C1
References
- General References
- Donnelley MA, Zhu ES, Thompson GR 3rd: Isavuconazole in the treatment of invasive aspergillosis and mucormycosis infections. Infect Drug Resist. 2016 Jun 2;9:79-86. doi: 10.2147/IDR.S81416. eCollection 2016. [Article]
- Kovanda LL, Desai AV, Lu Q, Townsend RW, Akhtar S, Bonate P, Hope WW: Isavuconazole Population Pharmacokinetic Analysis Using Nonparametric Estimation in Patients with Invasive Fungal Disease (Results from the VITAL Study). Antimicrob Agents Chemother. 2016 Jul 22;60(8):4568-76. doi: 10.1128/AAC.00514-16. Print 2016 Aug. [Article]
- Falci DR, Pasqualotto AC: Profile of isavuconazole and its potential in the treatment of severe invasive fungal infections. Infect Drug Resist. 2013 Oct 22;6:163-74. doi: 10.2147/IDR.S51340. [Article]
- EMA Label: Cresemba, Isavuconazole - European Medicines Agency - Europa EU [Link]
- External Links
- ChemSpider
- 5293682
- 1720882
- ChEBI
- 85979
- ChEMBL
- CHEMBL409153
- ZINC
- ZINC000001485935
- PDBe Ligand
- QKM
- Wikipedia
- Isavuconazonium
- PDB Entries
- 6ux0
- FDA label
- Download (851 KB)
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 dataNot Available Active Not Recruiting Not Available Population Modeling of Anti-infective Drugs 1 somestatus stop reason just information to hide Not Available Completed Not Available Invasive Aspergillosis / Mucormycosis 1 somestatus stop reason just information to hide Not Available Not Yet Recruiting Treatment Invasive Aspergillosis / Mucormycosis 1 somestatus stop reason just information to hide 4 Recruiting Treatment Invasive Fungal Infections 1 somestatus stop reason just information to hide 3 Completed Treatment Aspergillosis / Invasive Fungal Infections 2 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 40 mg Injection, powder, for solution Intravenous 200 mg Capsule Oral 100 mg Injection, solution, concentrate Intravenous 200 mg/1vial - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Not Available
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0162 mg/mL ALOGPS logP 3.46 ALOGPS logP 4.14 Chemaxon logS -4.4 ALOGPS pKa (Strongest Acidic) 12.59 Chemaxon pKa (Strongest Basic) 2.32 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 87.62 Å2 Chemaxon Rotatable Bond Count 6 Chemaxon Refractivity 123.94 m3·mol-1 Chemaxon Polarizability 42.74 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS splash10-03fu-7982000000-597a54125119fb75c437 Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-000i-0000900000-81033301bdb7f914e8a9 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-000i-0314900000-e1bc03d26517e9c0e771 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-00y0-8008900000-1f9a4bd5a1627314d87a Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-00di-9202300000-9102b611e3aeb1d35f19 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0f79-3985800000-33fe34fd7cb841867425 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0bu0-2900000000-a3d04c8f2c9a46bf20b6 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 189.66362 predictedDeepCCS 1.0 (2019) [M+H]+ 192.05916 predictedDeepCCS 1.0 (2019) [M+Na]+ 198.15154 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Not Available
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Sterol 14alpha-demethylase that plays a critical role in the third module of ergosterol biosynthesis pathway, being ergosterol the major sterol component in fungal membranes that participates in a variety of functions (By similarity). The third module or late pathway involves the ergosterol synthesis itself through consecutive reactions that mainly occur in the endoplasmic reticulum (ER) membrane (By similarity). In filamentous fungi, during the initial step of this module, lanosterol (lanosta-8,24-dien-3beta-ol) can be metabolized to eburicol (By similarity). Sterol 14alpha-demethylase catalyzes the three-step oxidative removal of the 14alpha-methyl group (C-32) of both these sterols in the form of formate, and converts eburicol and lanosterol to 14-demethyleburicol (4,4,24-trimethylergosta-8,14,24(28)-trienol) and 4,4-dimethyl-5alpha-cholesta-8,14,24-trien-3beta-ol, respectively, which are further metabolized by other enzymes in the pathway to ergosterol (By similarity). Can also use substrates not intrinsic to fungi, such as 24,25-dihydrolanosterol (DHL), producing 4,4-dimethyl-8,14-cholestadien-3-beta-ol, but at lower rates than the endogenous substrates (By similarity).
- Specific Function
- heme binding
- Gene Name
- ERG11
- Uniprot ID
- P50859
- Uniprot Name
- Lanosterol 14-alpha demethylase
- Molecular Weight
- 61304.95 Da
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- Curator comments
- IC50 of 19.44 μM in vitro (HEK293 cell line).
- General Function
- Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel (PubMed:10219239, PubMed:10753933, PubMed:10790218, PubMed:10837251, PubMed:11997281, PubMed:12063277, PubMed:18559421, PubMed:22314138, PubMed:22359612, PubMed:26363003, PubMed:27916661, PubMed:9230439, PubMed:9351446, PubMed:9765245). Channel properties are modulated by cAMP and subunit assembly (PubMed:10837251). Characterized by unusual gating kinetics by producing relatively small outward currents during membrane depolarization and large inward currents during subsequent repolarization which reflect a rapid inactivation during depolarization and quick recovery from inactivation but slow deactivation (closing) during repolarization (PubMed:10219239, PubMed:10753933, PubMed:10790218, PubMed:10837251, PubMed:11997281, PubMed:12063277, PubMed:18559421, PubMed:22314138, PubMed:22359612, PubMed:26363003, PubMed:27916661, PubMed:9230439, PubMed:9351446, PubMed:9765245). Channel properties are modulated by cAMP and subunit assembly (PubMed:10837251). Forms a stable complex with KCNE1 or KCNE2, and that this heteromultimerization regulates inward rectifier potassium channel activity (PubMed:10219239, PubMed:9230439)
- Specific Function
- delayed rectifier potassium channel activity
- Gene Name
- KCNH2
- Uniprot ID
- Q12809
- Uniprot Name
- Voltage-gated inwardly rectifying potassium channel KCNH2
- Molecular Weight
- 126653.52 Da
References
- Keirns J, Desai A, Kowalski D, Lademacher C, Mujais S, Parker B, Schneidkraut MJ, Townsend R, Wojtkowski T, Yamazaki T, Yen M, Kowey PR: QT Interval Shortening With Isavuconazole: In Vitro and In Vivo Effects on Cardiac Repolarization. Clin Pharmacol Ther. 2017 Jun;101(6):782-790. doi: 10.1002/cpt.620. Epub 2017 Feb 13. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- Curator comments
- IC50 was 6.57 μM in vitro (CHO cell line).
- General Function
- Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents (PubMed:11741969, PubMed:12176756, PubMed:12181424, PubMed:15454078, PubMed:15863612, PubMed:16299511, PubMed:17071743, PubMed:17224476, PubMed:20953164, PubMed:23677916, PubMed:24728418, PubMed:26253506, PubMed:27218670, PubMed:29078335, PubMed:29742403, PubMed:30023270, PubMed:30172029, PubMed:34163037, PubMed:7737988, PubMed:8099908, PubMed:8392192, PubMed:9013606, PubMed:9087614, PubMed:9607315). Mediates influx of calcium ions into the cytoplasm, and thereby triggers calcium release from the sarcoplasm (By similarity). Plays an important role in excitation-contraction coupling in the heart. Required for normal heart development and normal regulation of heart rhythm (PubMed:15454078, PubMed:15863612, PubMed:17224476, PubMed:24728418, PubMed:26253506). Required for normal contraction of smooth muscle cells in blood vessels and in the intestine. Essential for normal blood pressure regulation via its role in the contraction of arterial smooth muscle cells (PubMed:28119464). Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group (Probable)
- Specific Function
- alpha-actinin binding
- Gene Name
- CACNA1C
- Uniprot ID
- Q13936
- Uniprot Name
- Voltage-dependent L-type calcium channel subunit alpha-1C
- Molecular Weight
- 248974.1 Da
References
- Keirns J, Desai A, Kowalski D, Lademacher C, Mujais S, Parker B, Schneidkraut MJ, Townsend R, Wojtkowski T, Yamazaki T, Yen M, Kowey PR: QT Interval Shortening With Isavuconazole: In Vitro and In Vivo Effects on Cardiac Repolarization. Clin Pharmacol Ther. 2017 Jun;101(6):782-790. doi: 10.1002/cpt.620. Epub 2017 Feb 13. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- Curator comments
- IC50 was >30 μM in vitro (HEK293 cell line).
- General Function
- This potassium channel may be involved in the regulation of insulin secretion by glucose and/or neurotransmitters acting through G-protein-coupled receptors. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium
- Specific Function
- G-protein activated inward rectifier potassium channel activity
- Gene Name
- KCNJ6
- Uniprot ID
- P48051
- Uniprot Name
- G protein-activated inward rectifier potassium channel 2
- Molecular Weight
- 48450.96 Da
References
- Keirns J, Desai A, Kowalski D, Lademacher C, Mujais S, Parker B, Schneidkraut MJ, Townsend R, Wojtkowski T, Yamazaki T, Yen M, Kowey PR: QT Interval Shortening With Isavuconazole: In Vitro and In Vivo Effects on Cardiac Repolarization. Clin Pharmacol Ther. 2017 Jun;101(6):782-790. doi: 10.1002/cpt.620. Epub 2017 Feb 13. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- Curator comments
- IC50 was >30 μM in vitro (HEK293 cell line).
- General Function
- This receptor is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium (By similarity)
- Specific Function
- G-protein activated inward rectifier potassium channel activity
- Gene Name
- KCNJ9
- Uniprot ID
- Q92806
- Uniprot Name
- G protein-activated inward rectifier potassium channel 3
- Molecular Weight
- 44019.45 Da
References
- Keirns J, Desai A, Kowalski D, Lademacher C, Mujais S, Parker B, Schneidkraut MJ, Townsend R, Wojtkowski T, Yamazaki T, Yen M, Kowey PR: QT Interval Shortening With Isavuconazole: In Vitro and In Vivo Effects on Cardiac Repolarization. Clin Pharmacol Ther. 2017 Jun;101(6):782-790. doi: 10.1002/cpt.620. Epub 2017 Feb 13. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- Curator comments
- IC50 was >30 μM in vitro (HEK293 cell line).
- General Function
- This receptor is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by extracellular barium (By similarity). Subunit of ATP-sensitive potassium channels (KATP). Can form cardiac and smooth muscle-type KATP channels with ABCC9. KCNJ11 forms the channel pore while ABCC9 is required for activation and regulation
- Specific Function
- ankyrin binding
- Gene Name
- KCNJ11
- Uniprot ID
- Q14654
- Uniprot Name
- ATP-sensitive inward rectifier potassium channel 11
- Molecular Weight
- 43525.415 Da
References
- Keirns J, Desai A, Kowalski D, Lademacher C, Mujais S, Parker B, Schneidkraut MJ, Townsend R, Wojtkowski T, Yamazaki T, Yen M, Kowey PR: QT Interval Shortening With Isavuconazole: In Vitro and In Vivo Effects on Cardiac Repolarization. Clin Pharmacol Ther. 2017 Jun;101(6):782-790. doi: 10.1002/cpt.620. Epub 2017 Feb 13. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- Curator comments
- IC50 was >30 μM in vitro (CHO cell line).
- General Function
- Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes. Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane. Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel (PubMed:12130714). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation (PubMed:12130714). Homotetrameric channels display rapid activation and slow inactivation (PubMed:12130714, PubMed:8505626). Required for normal electrical conduction including formation of the infranodal ventricular conduction system and normal action potential configuration, as a result of its interaction with XIRP2 (By similarity). May play a role in regulating the secretion of insulin in normal pancreatic islets
- Specific Function
- alpha-actinin binding
- Gene Name
- KCNA5
- Uniprot ID
- P22460
- Uniprot Name
- Potassium voltage-gated channel subfamily A member 5
- Molecular Weight
- 67227.15 Da
References
- Keirns J, Desai A, Kowalski D, Lademacher C, Mujais S, Parker B, Schneidkraut MJ, Townsend R, Wojtkowski T, Yamazaki T, Yen M, Kowey PR: QT Interval Shortening With Isavuconazole: In Vitro and In Vivo Effects on Cardiac Repolarization. Clin Pharmacol Ther. 2017 Jun;101(6):782-790. doi: 10.1002/cpt.620. Epub 2017 Feb 13. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- Curator comments
- IC50 was 35.24 μM in vitro (HEK293 cell line).
- General Function
- Pore-forming (alpha) subunit of voltage-gated A-type potassium channels that mediates transmembrane potassium transport in excitable membranes, in brain and heart (PubMed:10200233, PubMed:17187064, PubMed:21349352, PubMed:22457051, PubMed:23280837, PubMed:23280838, PubMed:34997220, PubMed:9843794). In cardiomyocytes, may generate the transient outward potassium current I(To) (By similarity). In neurons, may conduct the transient subthreshold somatodendritic A-type potassium current (ISA) (By similarity). Kinetics properties are characterized by fast activation at subthreshold membrane potentials, rapid inactivation, and quick recovery from inactivation (PubMed:10200233, PubMed:17187064, PubMed:21349352, PubMed:22457051, PubMed:23280837, PubMed:23280838, PubMed:34997220, PubMed:9843794). Channel properties are modulated by interactions with regulatory subunits (PubMed:17187064, PubMed:34997220). Interaction with the regulatory subunits KCNIP1 or KCNIP2 modulates the channel gating kinetics namely channel activation and inactivation kinetics and rate of recovery from inactivation (PubMed:17187064, PubMed:34997220). Likewise, interaction with DPP6 modulates the channel gating kinetics namely channel activation and inactivation kinetics (PubMed:34997220)
- Specific Function
- A-type (transient outward) potassium channel activity
- Gene Name
- KCND3
- Uniprot ID
- Q9UK17
- Uniprot Name
- A-type voltage-gated potassium channel KCND3
- Molecular Weight
- 73450.53 Da
References
- Keirns J, Desai A, Kowalski D, Lademacher C, Mujais S, Parker B, Schneidkraut MJ, Townsend R, Wojtkowski T, Yamazaki T, Yen M, Kowey PR: QT Interval Shortening With Isavuconazole: In Vitro and In Vivo Effects on Cardiac Repolarization. Clin Pharmacol Ther. 2017 Jun;101(6):782-790. doi: 10.1002/cpt.620. Epub 2017 Feb 13. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- Curator comments
- IC50 was 24.03 μM in vitro (CHO cell line).
- General Function
- Potassium channel that plays an important role in a number of tissues, including heart, inner ear, stomach and colon (PubMed:10646604, PubMed:25441029). Associates with KCNE beta subunits that modulates current kinetics (PubMed:10646604, PubMed:11101505, PubMed:19687231, PubMed:8900283, PubMed:9108097, PubMed:9312006). Induces a voltage-dependent current by rapidly activating and slowly deactivating potassium-selective outward current (PubMed:10646604, PubMed:11101505, PubMed:25441029, PubMed:8900283, PubMed:9108097, PubMed:9312006). Promotes also a delayed voltage activated potassium current showing outward rectification characteristic (By similarity). During beta-adrenergic receptor stimulation participates in cardiac repolarization by associating with KCNE1 to form the I(Ks) cardiac potassium current that increases the amplitude and slows down the activation kinetics of outward potassium current I(Ks) (By similarity) (PubMed:10646604, PubMed:11101505, PubMed:8900283, PubMed:9108097, PubMed:9312006). Muscarinic agonist oxotremorine-M strongly suppresses KCNQ1/KCNE1 current (PubMed:10713961). When associated with KCNE3, forms the potassium channel that is important for cyclic AMP-stimulated intestinal secretion of chloride ions (PubMed:10646604). This interaction with KCNE3 is reduced by 17beta-estradiol, resulting in the reduction of currents (By similarity). During conditions of increased substrate load, maintains the driving force for proximal tubular and intestinal sodium ions absorption, gastric acid secretion, and cAMP-induced jejunal chloride ions secretion (By similarity). Allows the provision of potassium ions to the luminal membrane of the secretory canaliculus in the resting state as well as during stimulated acid secretion (By similarity). When associated with KCNE2, forms a heterooligomer complex leading to currents with an apparently instantaneous activation, a rapid deactivation process and a linear current-voltage relationship and decreases the amplitude of the outward current (PubMed:11101505). When associated with KCNE4, inhibits voltage-gated potassium channel activity (PubMed:19687231). When associated with KCNE5, this complex only conducts current upon strong and continued depolarization (PubMed:12324418). Also forms a heterotetramer with KCNQ5; has a voltage-gated potassium channel activity (PubMed:24855057). Binds with phosphatidylinositol 4,5-bisphosphate (PubMed:25037568). KCNQ1-KCNE2 channel associates with Na(+)-coupled myo-inositol symporter in the apical membrane of choroid plexus epithelium and regulates the myo-inositol gradient between blood and cerebrospinal fluid with an impact on neuron excitability
- Specific Function
- calmodulin binding
- Gene Name
- KCNQ1
- Uniprot ID
- P51787
- Uniprot Name
- Potassium voltage-gated channel subfamily KQT member 1
- Molecular Weight
- 74697.925 Da
References
- Keirns J, Desai A, Kowalski D, Lademacher C, Mujais S, Parker B, Schneidkraut MJ, Townsend R, Wojtkowski T, Yamazaki T, Yen M, Kowey PR: QT Interval Shortening With Isavuconazole: In Vitro and In Vivo Effects on Cardiac Repolarization. Clin Pharmacol Ther. 2017 Jun;101(6):782-790. doi: 10.1002/cpt.620. Epub 2017 Feb 13. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- Curator comments
- IC50 was 20.36 (tonic) and 14.87 (phasic) μM in vitro (CHO cell line).
- General Function
- Pore-forming subunit of Nav1.5, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes. Navs, also called VGSCs (voltage-gated sodium channels) or VDSCs (voltage-dependent sodium channels), operate by switching between closed and open conformations depending on the voltage difference across the membrane. In the open conformation they allow Na(+) ions to selectively pass through the pore, along their electrochemical gradient. The influx of Na(+) ions provokes membrane depolarization, initiating the propagation of electrical signals throughout cells and tissues (PubMed:1309946, PubMed:21447824, PubMed:23085483, PubMed:23420830, PubMed:25370050, PubMed:26279430, PubMed:26392562, PubMed:26776555). Nav1.5 is the predominant sodium channel expressed in myocardial cells and it is responsible for the initial upstroke of the action potential in cardiac myocytes, thereby initiating the heartbeat (PubMed:11234013, PubMed:11804990, PubMed:12569159, PubMed:1309946). Required for normal electrical conduction including formation of the infranodal ventricular conduction system and normal action potential configuration, as a result of its interaction with XIRP2 (By similarity)
- Specific Function
- ankyrin binding
- Gene Name
- SCN5A
- Uniprot ID
- Q14524
- Uniprot Name
- Sodium channel protein type 5 subunit alpha
- Molecular Weight
- 226937.475 Da
References
- Keirns J, Desai A, Kowalski D, Lademacher C, Mujais S, Parker B, Schneidkraut MJ, Townsend R, Wojtkowski T, Yamazaki T, Yen M, Kowey PR: QT Interval Shortening With Isavuconazole: In Vitro and In Vivo Effects on Cardiac Repolarization. Clin Pharmacol Ther. 2017 Jun;101(6):782-790. doi: 10.1002/cpt.620. Epub 2017 Feb 13. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- 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
- Jenks JD, Salzer HJ, Prattes J, Krause R, Buchheidt D, Hoenigl M: Spotlight on isavuconazole in the treatment of invasive aspergillosis and mucormycosis: design, development, and place in therapy. Drug Des Devel Ther. 2018 Apr 30;12:1033-1044. doi: 10.2147/DDDT.S145545. eCollection 2018. [Article]
- Wilson DT, Dimondi VP, Johnson SW, Jones TM, Drew RH: Role of isavuconazole in the treatment of invasive fungal infections. Ther Clin Risk Manag. 2016 Aug 3;12:1197-206. doi: 10.2147/TCRM.S90335. eCollection 2016. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- 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
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- InhibitorInducer
- 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
- Wilson DT, Dimondi VP, Johnson SW, Jones TM, Drew RH: Role of isavuconazole in the treatment of invasive fungal infections. Ther Clin Risk Manag. 2016 Aug 3;12:1197-206. doi: 10.2147/TCRM.S90335. eCollection 2016. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- InhibitorInducer
- Curator comments
- Data supporting this enzyme action are limited to in vitro studies.
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and steroids (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). 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:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:15766564, PubMed:19965576, PubMed:7574697, PubMed:9866708). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Exhibits low catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes bisallylic hydroxylation and hydroxylation with double-bond migration of polyunsaturated fatty acids (PUFA) (PubMed:9435160, PubMed:9866708). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan (PubMed:25994031)
- Specific Function
- (R)-limonene 6-monooxygenase activity
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- Desai A, Yamazaki T, Dietz AJ, Kowalski D, Lademacher C, Pearlman H, Akhtar S, Townsend R: Pharmacokinetic and Pharmacodynamic Evaluation of the Drug-Drug Interaction Between Isavuconazole and Warfarin in Healthy Subjects. Clin Pharmacol Drug Dev. 2017 Jan;6(1):86-92. doi: 10.1002/cpdd.283. Epub 2016 Aug 4. [Article]
- Wilson DT, Dimondi VP, Johnson SW, Jones TM, Drew RH: Role of isavuconazole in the treatment of invasive fungal infections. Ther Clin Risk Manag. 2016 Aug 3;12:1197-206. doi: 10.2147/TCRM.S90335. eCollection 2016. [Article]
- Isavuconazole FDA label [File]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of polyunsaturated fatty acids (PUFA) (PubMed:18577768, PubMed:19965576, PubMed:20972997). 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:18577768, PubMed:19965576, PubMed:20972997). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates PUFA specifically at the omega-1 position (PubMed:18577768). Catalyzes the epoxidation of double bonds of PUFA (PubMed:19965576, PubMed:20972997). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Hydroxylates fenbendazole at the 4' position (PubMed:23959307)
- Specific Function
- (R)-limonene 6-monooxygenase activity
- Gene Name
- CYP2C19
- Uniprot ID
- P33261
- Uniprot Name
- Cytochrome P450 2C19
- Molecular Weight
- 55944.565 Da
References
- Wilson DT, Dimondi VP, Johnson SW, Jones TM, Drew RH: Role of isavuconazole in the treatment of invasive fungal infections. Ther Clin Risk Manag. 2016 Aug 3;12:1197-206. doi: 10.2147/TCRM.S90335. eCollection 2016. [Article]
- Miceli MH, Kauffman CA: Isavuconazole: A New Broad-Spectrum Triazole Antifungal Agent. Clin Infect Dis. 2015 Nov 15;61(10):1558-65. doi: 10.1093/cid/civ571. Epub 2015 Jul 15. [Article]
- Peixoto D, Gagne LS, Hammond SP, Gilmore ET, Joyce AC, Soiffer RJ, Marty FM: Isavuconazole treatment of a patient with disseminated mucormycosis. J Clin Microbiol. 2014 Mar;52(3):1016-9. doi: 10.1128/JCM.03176-13. Epub 2014 Jan 8. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of fatty acids, steroids and retinoids (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, 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) (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:19965576, PubMed:20972997). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:18698000, PubMed:21289075). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Catalyzes the oxidative transformations of all-trans retinol to all-trans retinal, a precursor for the active form all-trans-retinoic acid (PubMed:10681376). Also involved in the oxidative metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants
- Specific Function
- anandamide 11,12 epoxidase activity
- Gene Name
- CYP2D6
- Uniprot ID
- P10635
- Uniprot Name
- Cytochrome P450 2D6
- Molecular Weight
- 55768.94 Da
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inducer
- 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
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:12181437, PubMed:15470161, PubMed:15472229, PubMed:18004212, PubMed:18052087, PubMed:18674515, PubMed:19545173). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol and estrone (PubMed:15472229). Also catalyzes the glucuronidation of the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist caderastan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (SN-38), the pharmacologically active metabolite of the anticancer drug irinotecan (PubMed:12181437, PubMed:20610558). Also metabolizes mycophenolate, an immunosuppressive agent (PubMed:15470161, PubMed:18004212)
- Specific Function
- enzyme binding
- Gene Name
- UGT1A9
- Uniprot ID
- O60656
- Uniprot Name
- UDP-glucuronosyltransferase 1A9
- Molecular Weight
- 59940.495 Da
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:15472229, PubMed:16595710, PubMed:18004212, PubMed:18052087, PubMed:18674515, PubMed:18719240, PubMed:19545173, PubMed:23288867). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:15472229, PubMed:16595710, PubMed:23288867). Catalyzes the glucuronidation of endogenous steroid hormones such as androgens and estrogens (PubMed:15472229, PubMed:16595710, PubMed:18719240, PubMed:23288867). Produces dihydrotestosterone (DHT) diglucuronide from the DHT after two subsequent glucoronidation steps (PubMed:16595710). Also catalyzes the glucuronidation of the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist caderastan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Also metabolizes mycophenolate, an immunosuppressive agent (PubMed:15470161, PubMed:18004212)
- Specific Function
- enzyme binding
- Gene Name
- UGT1A8
- Uniprot ID
- Q9HAW9
- Uniprot Name
- UDP-glucuronosyltransferase 1A8
- Molecular Weight
- 59741.035 Da
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- 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
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- Broad substrate specificity ATP-binding cassette transporter ABCG2
- Molecular Weight
- 72313.47 Da
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- 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
Drug created at October 17, 2016 21:27 / Updated at February 21, 2021 18:53