Identification

Name
Isavuconazole
Accession Number
DB11633
Type
Small Molecule
Groups
Approved, Investigational
Description

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].

Its prodrug, Isavuconazonium, is commonly used as an active ingredient in commercially available formulations due to low water solubility of isavuconazole. 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.

Structure
Thumb
Synonyms
  • isavuconazol
  • isavuconazole
  • isavuconazolum
External IDs
BAL-4815
Categories
UNII
60UTO373KE
CAS number
241479-67-4
Weight
Average: 437.47
Monoisotopic: 437.112187687
Chemical Formula
C22H17F2N5OS
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
[H][C@](C)(C1=NC(=CS1)C1=CC=C(C=C1)C#N)[C@](O)(CN1C=NC=N1)C1=C(F)C=CC(F)=C1

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].
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].

TargetActionsOrganism
ALanosterol 14-alpha demethylase
inhibitor
Yeast
NPotassium voltage-gated channel subfamily H member 2
inhibitor
Human
NVoltage-dependent L-type calcium channel subunit alpha-1C
inhibitor
Human
NG protein-activated inward rectifier potassium channel 2
inhibitor
Human
NG protein-activated inward rectifier potassium channel 3
inhibitor
Human
NATP-sensitive inward rectifier potassium channel 11
inhibitor
Human
NPotassium voltage-gated channel subfamily A member 5
inhibitor
Human
NPotassium voltage-gated channel subfamily D member 3
inhibitor
Human
NPotassium voltage-gated channel subfamily KQT member 1
inhibitor
Human
NSodium channel protein type 5 subunit alpha
inhibitor
Human
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].

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].

Affected organisms
  • Aspergillis, Candida and other fungi
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be increased when combined with Isavuconazole.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Isavuconazole.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Isavuconazole.
AbirateroneThe serum concentration of Abiraterone can be increased when it is combined with Isavuconazole.
AcebutololThe serum concentration of Acebutolol can be increased when it is combined with Isavuconazole.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Isavuconazole.
AcenocoumarolThe metabolism of Acenocoumarol can be increased when combined with Isavuconazole.
AcetaminophenThe serum concentration of Acetaminophen can be increased when it is combined with Isavuconazole.
AcetaminophenThe serum concentration of Acetaminophen can be increased when it is combined with Isavuconazole.
Acetylsalicylic acidThe serum concentration of Acetylsalicylic acid can be increased when it is combined with Isavuconazole.
Food Interactions
Not Available

References

General References
  1. 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. [PubMed:27330318]
  2. 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. [PubMed:27185799]
  3. 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. [PubMed:24187505]
  4. EMA Label: Cresemba, Isavuconazole - European Medicines Agency - Europa EU [Link]
External Links
ChemSpider
5293682
ChEBI
85979
ChEMBL
CHEMBL409153
Wikipedia
Isavuconazonium
ATC Codes
J02AC05 — Isavuconazole
FDA label
Download (851 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Adult Volunteers / Pharmacokinetics of Dextromethorphan / Pharmacokinetics of Isavuconazole1
1CompletedNot AvailableHealthy Adult Volunteers / Pharmacokinetics of Isavuconazole / Pharmacokinetics of Ketoconazole1
1CompletedNot AvailableHealthy Volunteers1
1CompletedNot AvailableHealthy Volunteers / Pharmacodynamics of Warfarin / Pharmacokinetics of Isavuconazole / Pharmacokinetics of S- and R-warfarin1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of 7-hydroxymethotrexate / Pharmacokinetics of Isavuconazole / Pharmacokinetics of Methotrexate1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Atorvastatin / Pharmacokinetics of Isavuconazole1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of BAL4815 / Pharmacokinetics of BAL87281
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Bupropion / Pharmacokinetics of Isavuconazole1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Digoxin / Pharmacokinetics of Isavuconazole1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Ethinyl Estradiol and Norethindrone / Pharmacokinetics of Isavuconazole1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Isavuconazole1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Isavuconazole / Pharmacokinetics of Lopinavir/Ritonavir1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Isavuconazole / Pharmacokinetics of Metformin1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Isavuconazole / Pharmacokinetics of Methadone1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Isavuconazole / Pharmacokinetics of Midazolam1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Isavuconazole / Pharmacokinetics of Plasma Mycophenolic Acid (MPA) / Pharmacokinetics of Plasma Phenolic Glucuronide of MPA (MPAG)1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Isavuconazole / Pharmacokinetics of Prednisolone1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Isavuconazole / Pharmacokinetics of Sirolimus1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Isavuconazole / Pharmacokinetics of Tacrolimus1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Isavuconazole / Renal Impaired1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Isavuconazole / Safety and Tolerability in Elderly1
1CompletedBasic ScienceHealthy Volunteers / Pharmacokinetics of Caffeine / Pharmacokinetics of Repaglinide1
1CompletedBasic ScienceHealthy Volunteers / Pharmacokinetics of Isavuconazole1
2RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML) / Myelodysplastic Syndrome1
2RecruitingTreatmentMalignancies, Hematologic / Myeloproliferative Disorders1
2, 3CompletedPreventionLeukemia Acute Myeloid Leukemia (AML)1
3CompletedTreatmentAspergillosis / Invasive Fungal Infections2
3CompletedTreatmentCandidemia / Candidiasis, Invasive / Mycoses1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0162 mg/mLALOGPS
logP3.46ALOGPS
logP4.14ChemAxon
logS-4.4ALOGPS
pKa (Strongest Acidic)12.61ChemAxon
pKa (Strongest Basic)2.46ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area87.62 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity123.94 m3·mol-1ChemAxon
Polarizability42.61 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
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

Taxonomy

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
Phenylpropane / Benzonitrile / 2,4-disubstituted 1,3-thiazole / Fluorobenzene / Halobenzene / Aryl fluoride / Aryl halide / Azole / Heteroaromatic compound / 1,2,4-triazole
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)

Targets

Kind
Protein
Organism
Yeast
Pharmacological action
Yes
Actions
Inhibitor
General Function
Sterol 14-demethylase activity
Specific Function
Catalyzes C14-demethylation of lanosterol which is critical for ergosterol biosynthesis. It transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol (By similarity).
Gene Name
ERG11
Uniprot ID
P50859
Uniprot Name
Lanosterol 14-alpha demethylase
Molecular Weight
61304.95 Da
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
Curator comments
IC50 of 19.44 μM in vitro (HEK293 cell line).
General Function
Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Specific Function
Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the ...
Gene Name
KCNH2
Uniprot ID
Q12809
Uniprot Name
Potassium voltage-gated channel subfamily H member 2
Molecular Weight
126653.52 Da
References
  1. 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. [PubMed:28074556]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
Curator comments
IC50 was 6.57 μM in vitro (CHO cell line).
General Function
Voltage-gated calcium channel activity
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1C
Uniprot ID
Q13936
Uniprot Name
Voltage-dependent L-type calcium channel subunit alpha-1C
Molecular Weight
248974.1 Da
References
  1. 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. [PubMed:28074556]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
Curator comments
IC50 was >30 μM in vitro (HEK293 cell line).
General Function
Inward rectifier potassium channel activity
Specific 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...
Gene Name
KCNJ6
Uniprot ID
P48051
Uniprot Name
G protein-activated inward rectifier potassium channel 2
Molecular Weight
48450.96 Da
References
  1. 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. [PubMed:28074556]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
Curator comments
IC50 was >30 μM in vitro (HEK293 cell line).
General Function
G-protein activated inward rectifier potassium channel activity
Specific 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 ...
Gene Name
KCNJ9
Uniprot ID
Q92806
Uniprot Name
G protein-activated inward rectifier potassium channel 3
Molecular Weight
44019.45 Da
References
  1. 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. [PubMed:28074556]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
Curator comments
IC50 was >30 μM in vitro (HEK293 cell line).
General Function
Voltage-gated potassium channel activity
Specific 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 ...
Gene Name
KCNJ11
Uniprot ID
Q14654
Uniprot Name
ATP-sensitive inward rectifier potassium channel 11
Molecular Weight
43540.375 Da
References
  1. 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. [PubMed:28074556]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
Curator comments
IC50 was >30 μM in vitro (CHO cell line).
General Function
Voltage-gated potassium channel activity involved in sa node cell action potential repolarization
Specific 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...
Gene Name
KCNA5
Uniprot ID
P22460
Uniprot Name
Potassium voltage-gated channel subfamily A member 5
Molecular Weight
67227.15 Da
References
  1. 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. [PubMed:28074556]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
Curator comments
IC50 was 35.24 μM in vitro (HEK293 cell line).
General Function
Metal ion binding
Specific Function
Pore-forming (alpha) subunit of voltage-gated rapidly inactivating A-type potassium channels. May contribute to I(To) current in heart and I(Sa) current in neurons. Channel properties are modulated...
Gene Name
KCND3
Uniprot ID
Q9UK17
Uniprot Name
Potassium voltage-gated channel subfamily D member 3
Molecular Weight
73450.53 Da
References
  1. 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. [PubMed:28074556]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
Curator comments
IC50 was 24.03 μM in vitro (CHO cell line).
General Function
Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Specific Function
Potassium channel that plays an important role in a number of tissues, including heart, inner ear, stomach and colon (By similarity) (PubMed:10646604). Associates with KCNE beta subunits that modul...
Gene Name
KCNQ1
Uniprot ID
P51787
Uniprot Name
Potassium voltage-gated channel subfamily KQT member 1
Molecular Weight
74697.925 Da
References
  1. 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. [PubMed:28074556]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
Curator comments
IC50 was 20.36 (tonic) and 14.87 (phasic) μM in vitro (CHO cell line).
General Function
Voltage-gated sodium channel activity involved in sa node cell action potential
Specific Function
This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the pr...
Gene Name
SCN5A
Uniprot ID
Q14524
Uniprot Name
Sodium channel protein type 5 subunit alpha
Molecular Weight
226937.475 Da
References
  1. 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. [PubMed:28074556]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
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
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
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
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Inducer
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
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Inducer
Curator comments
Data supporting this enzyme action are limited to in vitro studies.
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
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. 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. [PubMed:27278712]
  2. Isavuconazole FDA label [File]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
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 im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. 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. [PubMed:27536124]
  2. 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. [PubMed:26179012]
  3. 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. [PubMed:24403304]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
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
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks trans...
Gene Name
UGT1A9
Uniprot ID
O60656
Uniprot Name
UDP-glucuronosyltransferase 1-9
Molecular Weight
59940.495 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg...
Gene Name
UGT1A8
Uniprot ID
Q9HAW9
Uniprot Name
UDP-glucuronosyltransferase 1-8
Molecular Weight
59741.035 Da

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
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
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
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

Drug created on October 17, 2016 15:27 / Updated on October 21, 2018 20:38