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Identification
NameGallium nitrate
Accession NumberDB05260
TypeSmall Molecule
GroupsApproved, Investigational
Description

Gallium nitrate is a drug that is used to treat hyper-calcemia, or too much calcium in the blood. This condition may occur when individuals develop various types of cancer. Gallium nitrate is also known by the common brand name Ganite.

Structure
Thumb
Synonyms
Gallium nitrate (anhydrous)
Nitric acid, gallium salt, anhydrate
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Ganiteinjection, solution, concentrate25 mg/mLintravenousGenta Incorporated2003-09-17Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Gallium nitrate nonahydrate
135886-70-3
Thumb
  • InChI Key: VALBLFFHYPYRDR-UHFFFAOYSA-N
  • Monoisotopic Mass: 423.03106
  • Average Mass: 423.918
DBSALT001854
Categories
UNIIY2V2R4W9TQ
CAS number13494-90-1
WeightAverage: 255.738
Monoisotopic: 254.889034525
Chemical FormulaGaN3O9
InChI KeyInChIKey=CHPZKNULDCNCBW-UHFFFAOYSA-N
InChI
InChI=1S/Ga.3NO3/c;3*2-1(3)4/q+3;3*-1
IUPAC Name
gallium(3+) ion trinitrate
SMILES
[Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O
Taxonomy
DescriptionThis compound belongs to the class of inorganic compounds known as post-transition metal nitrates. These are inorganic compounds in which the largest oxoanion is nitrate, and in which the heaviest atom not in an oxoanion is a post-transition metal.
KingdomInorganic compounds
Super ClassMixed metal/non-metal compounds
ClassPost-transition metal oxoanionic compounds
Sub ClassPost-transition metal nitrates
Direct ParentPost-transition metal nitrates
Alternative Parents
Substituents
  • Post-transition metal nitrate
  • Inorganic post-transition metal salt
  • Inorganic oxide
  • Inorganic salt
  • Acyclic compound
Molecular FrameworkAcyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationFor the treatment of hypercalcemia. Also intended for the treatment of non-hodgkin's lymphoma.
PharmacodynamicsGallium nitrate exerts hypocalcemic effect by inhibiting calcium resorption from bone, possibly by stabilizing bone matrix, thereby reducing increased bone turnover. Gallium nitrate inhibits the growth of various lymphoma cell lines in vitro and exhibits antitumor activity in patients with lymphoma. The mechanism(s) of cytotoxicity is (are) only partly understood but appears to involve a two-step process: (1) targeting of gallium to cells, and (2) acting on multiple, specific intracellular processes. Gallium shares certain chemical properties with iron; therefore, it binds avidly to the iron transport protein transferrin. Transferrin-gallium complexes preferentially target cells that express transferrin receptors on their surface. Expression of transferrin receptors is particularly high on lymphoma cells. Cellular uptake of the gallium-transferrin complex leads to inhibition of cellular proliferation primarily via disruption of iron transport and homeostasis and blockade of ribonucleotide reductase. Recent studies have shown that cellular uptake of gallium leads to activation of caspases and induction of apoptosis. In phase II trials in patients with relapsed or refractory lymphoma, the antitumor activity of gallium nitrate is similar to, or better than, that of other commonly used chemotherapeutic agents.
Mechanism of actionGallium nitrate is believed to exert a hypocalcemic effect by inhibiting calcium resorption from bone. Gallium nitrate localizes preferentially where bone resorption and remodeling is occurring, and inhibits osteoclast activity. Inhibition of resorption may occur via a reduction in increased bone turnover. It seems to enhance hydroxyapatite function, inhibit osteocalcin, and inhibit the vacuolar ATPase on the osteoclast ruffled membrane. All these aid in the reduction of bone resorption.
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
Route of eliminationGallium nitrate is not metabolized either by the liver or the kidney and appears to be significantly excreted via the kidney.
Half lifeAlpha: 1 hour. Beta: 24 hours, but lengthens to 72 to 115 hours with prolonged intravenous infusion.
Clearance
  • 0.15 L/hr/kg [cancer patients receiving daily infusion of gallium nitrate at a dose of 200 mg/m2 for 5 or 7 days]
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.7952
Blood Brain Barrier+0.9337
Caco-2 permeable-0.5678
P-glycoprotein substrateNon-substrate0.8817
P-glycoprotein inhibitor INon-inhibitor0.927
P-glycoprotein inhibitor IINon-inhibitor0.984
Renal organic cation transporterNon-inhibitor0.9378
CYP450 2C9 substrateNon-substrate0.8511
CYP450 2D6 substrateNon-substrate0.8463
CYP450 3A4 substrateNon-substrate0.6475
CYP450 1A2 substrateNon-inhibitor0.7481
CYP450 2C9 inhibitorNon-inhibitor0.8894
CYP450 2D6 inhibitorNon-inhibitor0.9223
CYP450 2C19 inhibitorNon-inhibitor0.8364
CYP450 3A4 inhibitorNon-inhibitor0.928
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9678
Ames testAMES toxic0.6249
CarcinogenicityCarcinogens 0.7056
BiodegradationReady biodegradable0.9392
Rat acute toxicity2.6296 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6413
hERG inhibition (predictor II)Non-inhibitor0.9681
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Injection, solution, concentrateintravenous25 mg/mL
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
logP0.028ChemAxon
pKa (Strongest Acidic)-1.4ChemAxon
pKa (Strongest Basic)-6.1ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area68.88 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity9.85 m3·mol-1ChemAxon
Polarizability3.24 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General References
  1. Yang M, Kroft SH, Chitambar CR: Gene expression analysis of gallium-resistant and gallium-sensitive lymphoma cells reveals a role for metal-responsive transcription factor-1, metallothionein-2A, and zinc transporter-1 in modulating the antineoplastic activity of gallium nitrate. Mol Cancer Ther. 2007 Feb;6(2):633-43. [PubMed:17308060 ]
  2. Leyland-Jones B: Treating cancer-related hypercalcemia with gallium nitrate. J Support Oncol. 2004 Nov-Dec;2(6):509-16. [PubMed:15605917 ]
  3. Chitambar CR: Apoptotic mechanisms of gallium nitrate: basic and clinical investigations. Oncology (Williston Park). 2004 Nov;18(13 Suppl 10):39-44. [PubMed:15651176 ]
  4. Cvitkovic F, Armand JP, Tubiana-Hulin M, Rossi JF, Warrell RP Jr: Randomized, double-blind, phase II trial of gallium nitrate compared with pamidronate for acute control of cancer-related hypercalcemia. Cancer J. 2006 Jan-Feb;12(1):47-53. [PubMed:16613662 ]
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (8.19 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor
Specific Function:
Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides. Inhibits Wnt signaling.
Gene Name:
RRM2
Uniprot ID:
P31350
Molecular Weight:
44877.25 Da
References
  1. Chitambar CR: Apoptotic mechanisms of gallium nitrate: basic and clinical investigations. Oncology (Williston Park). 2004 Nov;18(13 Suppl 10):39-44. [PubMed:15651176 ]
  2. Narasimhan J, Antholine WE, Chitambar CR: Effect of gallium on the tyrosyl radical of the iron-dependent M2 subunit of ribonucleotide reductase. Biochem Pharmacol. 1992 Dec 15;44(12):2403-8. [PubMed:1335254 ]
  3. Straus DJ: Gallium nitrate in the treatment of lymphoma. Semin Oncol. 2003 Apr;30(2 Suppl 5):25-33. [PubMed:12776257 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Proton-transporting atpase activity, rotational mechanism
Specific Function:
Non-catalytic subunit of the peripheral V1 complex of vacuolar ATPase. V-ATPase is responsible for acidifying a variety of intracellular compartments in eukaryotic cells.
Gene Name:
ATP6V1B2
Uniprot ID:
P21281
Molecular Weight:
56500.21 Da
References
  1. Bockman R: The effects of gallium nitrate on bone resorption. Semin Oncol. 2003 Apr;30(2 Suppl 5):5-12. [PubMed:12776254 ]
  2. Mattsson JP, Skyman C, Palokangas H, Vaananen KH, Keeling DJ: Characterization and cellular distribution of the osteoclast ruffled membrane vacuolar H+-ATPase B-subunit using isoform-specific antibodies. J Bone Miner Res. 1997 May;12(5):753-60. [PubMed:9144341 ]
  3. Jakupec MA, Keppler BK: Gallium and other main group metal compounds as antitumor agents. Met Ions Biol Syst. 2004;42:425-62. [PubMed:15206110 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Structural molecule activity
Specific Function:
Constitutes 1-2% of the total bone protein. It binds strongly to apatite and calcium.
Gene Name:
BGLAP
Uniprot ID:
P02818
Molecular Weight:
10962.445 Da
References
  1. Jenis LG, Waud CE, Stein GS, Lian JB, Baran DT: Effect of gallium nitrate in vitro and in normal rats. J Cell Biochem. 1993 Jul;52(3):330-6. [PubMed:8366144 ]
  2. Guidon PT Jr, Salvatori R, Bockman RS: Gallium nitrate regulates rat osteoblast expression of osteocalcin protein and mRNA levels. J Bone Miner Res. 1993 Jan;8(1):103-12. [PubMed:8381250 ]
Kind
Small molecule
Organism
Human
Pharmacological action
yes
Actions
modulator
References
  1. Bockman R: The effects of gallium nitrate on bone resorption. Semin Oncol. 2003 Apr;30(2 Suppl 5):5-12. [PubMed:12776254 ]
Kind
Protein
Organism
Shewanella sp.
Pharmacological action
unknown
Actions
inhibitor
General Function:
Protein tyrosine phosphatase activity
Specific Function:
Not Available
Gene Name:
PPI
Uniprot ID:
Q9S427
Molecular Weight:
40814.26 Da
References
  1. Chitambar CR: Apoptotic mechanisms of gallium nitrate: basic and clinical investigations. Oncology (Williston Park). 2004 Nov;18(13 Suppl 10):39-44. [PubMed:15651176 ]
  2. Berggren MM, Burns LA, Abraham RT, Powis G: Inhibition of protein tyrosine phosphatase by the antitumor agent gallium nitrate. Cancer Res. 1993 Apr 15;53(8):1862-6. [PubMed:8467506 ]
  3. Straus DJ: Gallium nitrate in the treatment of lymphoma. Semin Oncol. 2003 Apr;30(2 Suppl 5):25-33. [PubMed:12776257 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Protein domain specific binding
Specific Function:
Potent proinflammatory cytokine. Initially discovered as the major endogenous pyrogen, induces prostaglandin synthesis, neutrophil influx and activation, T-cell activation and cytokine production, B-cell activation and antibody production, and fibroblast proliferation and collagen production. Promotes Th17 differentiation of T-cells.
Gene Name:
IL1B
Uniprot ID:
P01584
Molecular Weight:
30747.7 Da
References
  1. Eby G: Elimination of arthritis pain and inflammation for over 2 years with a single 90 min, topical 14% gallium nitrate treatment: case reports and review of actions of gallium III. Med Hypotheses. 2005;65(6):1136-41. Epub 2005 Aug 24. [PubMed:16122880 ]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Transferrin receptor binding
Specific Function:
Transferrins are iron binding transport proteins which can bind two Fe(3+) ions in association with the binding of an anion, usually bicarbonate. It is responsible for the transport of iron from sites of absorption and heme degradation to those of storage and utilization. Serum transferrin may also have a further role in stimulating cell proliferation.
Gene Name:
TF
Uniprot ID:
P02787
Molecular Weight:
77063.195 Da
References
  1. Groessl M, Bytzek A, Hartinger CG: The serum protein binding of pharmacologically active gallium(III) compounds assessed by hyphenated CE-MS techniques. Electrophoresis. 2009 Aug;30(15):2720-7. doi: 10.1002/elps.200800745. [PubMed:19621374 ]
  2. Bernstein LR, Tanner T, Godfrey C, Noll B: Chemistry and pharmacokinetics of gallium maltolate, a compound with high oral gallium bioavailability. Met Based Drugs. 2000;7(1):33-47. doi: 10.1155/MBD.2000.33. [PubMed:18475921 ]
  3. Davies NP, Suryo Rahmanto Y, Chitambar CR, Richardson DR: Resistance to the antineoplastic agent gallium nitrate results in marked alterations in intracellular iron and gallium trafficking: identification of novel intermediates. J Pharmacol Exp Ther. 2006 Apr;317(1):153-62. Epub 2005 Dec 22. [PubMed:16373528 ]

Transporters

Kind
Protein group
Organism
Human
Pharmacological action
yes
General Function:
Virus receptor activity
Specific Function:
Cellular uptake of iron occurs via receptor-mediated endocytosis of ligand-occupied transferrin receptor into specialized endosomes. Endosomal acidification leads to iron release. The apotransferrin-receptor complex is then recycled to the cell surface with a return to neutral pH and the concomitant loss of affinity of apotransferrin for its receptor. Transferrin receptor is necessary for development of erythrocytes and the nervous system (By similarity). A second ligand, the heditary hemochromatosis protein HFE, competes for binding with transferrin for an overlapping C-terminal binding site.(Microbial infection) Acts as a receptor for new-world arenaviruses: Guanarito, Junin and Machupo virus.
Components:
NameUniProt IDDetails
Transferrin receptor protein 1P02786 Details
Transferrin receptor protein 2Q9UP52 Details
References
  1. Chitambar CR: Apoptotic mechanisms of gallium nitrate: basic and clinical investigations. Oncology (Williston Park). 2004 Nov;18(13 Suppl 10):39-44. [PubMed:15651176 ]
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Drug created on November 18, 2007 11:22 / Updated on August 17, 2016 12:24