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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
SynonymsNot Available
SaltsNot Available
Brand names
NameCompany
GaniteGenta inc.
Brand mixturesNot Available
CategoriesNot Available
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 tris(nitrooxidane)
SMILES
[Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O
Mass SpecNot Available
Taxonomy
KingdomInorganic Compounds
SuperclassMixed Metal/Non-metal Compounds
ClassPost-transition Metal Oxoanionic Compounds
SubclassPost-transition Metal Nitrates
Direct parentPost-transition Metal Nitrates
Alternative parentsOrganic Nitric Acids; Nitro Compounds
Substituentsorganic nitric acid or derivative; organic nitric acid; nitro compound
Classification descriptionThis compound belongs to the 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.
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.
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism
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
Property Value Probability
Human Intestinal Absorption + 0.7952
Blood Brain Barrier + 0.9337
Caco-2 permeable - 0.5678
P-glycoprotein substrate Non-substrate 0.8817
P-glycoprotein inhibitor I Non-inhibitor 0.927
P-glycoprotein inhibitor II Non-inhibitor 0.984
Renal organic cation transporter Non-inhibitor 0.9378
CYP450 2C9 substrate Non-substrate 0.8511
CYP450 2D6 substrate Non-substrate 0.8463
CYP450 3A4 substrate Non-substrate 0.6475
CYP450 1A2 substrate Non-inhibitor 0.7481
CYP450 2C9 substrate Non-inhibitor 0.8894
CYP450 2D6 substrate Non-inhibitor 0.9223
CYP450 2C19 substrate Non-inhibitor 0.8364
CYP450 3A4 substrate Non-inhibitor 0.928
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9678
Ames test AMES toxic 0.6249
Carcinogenicity Carcinogens 0.7056
Biodegradation Ready biodegradable 0.9392
Rat acute toxicity 2.6296 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.6413
hERG inhibition (predictor II) Non-inhibitor 0.9681
Pharmacoeconomics
Manufacturers
  • Genta inc
PackagersNot Available
Dosage formsNot Available
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 area68.88ChemAxon
rotatable bond count0ChemAxon
refractivity9.85ChemAxon
polarizability3.24ChemAxon
number of rings0ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  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
  2. Leyland-Jones B: Treating cancer-related hypercalcemia with gallium nitrate. J Support Oncol. 2004 Nov-Dec;2(6):509-16. Pubmed
  3. Chitambar CR: Apoptotic mechanisms of gallium nitrate: basic and clinical investigations. Oncology (Williston Park). 2004 Nov;18(13 Suppl 10):39-44. Pubmed
  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
External Links
ResourceLink
PubChem Compound61635
PubChem Substance46508923
ChemSpider55543
Therapeutic Targets DatabaseDAP001096
PharmGKBPA164781198
Drugs.comhttp://www.drugs.com/cdi/gallium.html
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(8.19 KB)
Interactions
Drug Interactions
Drug
VancomycinAdditive nephrotoxic effects may occur. Avoid concomitant therapy.
Food InteractionsNot Available

1. Ribonucleoside-diphosphate reductase subunit M2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Ribonucleoside-diphosphate reductase subunit M2 P31350 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
  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
  3. Straus DJ: Gallium nitrate in the treatment of lymphoma. Semin Oncol. 2003 Apr;30(2 Suppl 5):25-33. Pubmed

2. V-type proton ATPase subunit B, brain isoform

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
V-type proton ATPase subunit B, brain isoform P21281 Details

References:

  1. Bockman R: The effects of gallium nitrate on bone resorption. Semin Oncol. 2003 Apr;30(2 Suppl 5):5-12. Pubmed
  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
  3. Jakupec MA, Keppler BK: Gallium and other main group metal compounds as antitumor agents. Met Ions Biol Syst. 2004;42:425-62. Pubmed

3. Osteocalcin

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Osteocalcin P02818 Details

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
  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

4. Hydroxylapatite

Kind: small molecule

Organism: Human

Pharmacological action: yes

Actions: modulator

Components

Name UniProt ID Details

References:

  1. Bockman R: The effects of gallium nitrate on bone resorption. Semin Oncol. 2003 Apr;30(2 Suppl 5):5-12. Pubmed

5. Protein-tyrosine-phosphatase

Kind: protein

Organism: Shewanella sp.

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Protein-tyrosine-phosphatase Q9S427 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
  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
  3. Straus DJ: Gallium nitrate in the treatment of lymphoma. Semin Oncol. 2003 Apr;30(2 Suppl 5):25-33. Pubmed

6. Interleukin-1 beta

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Interleukin-1 beta P01584 Details

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

1. Serotransferrin

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Serotransferrin P02787 Details

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. Pubmed
  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. Pubmed
  3. Davies NP, Rahmanto YS, 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

1. Transferrin receptor

Kind: protein group

Organism: Human

Pharmacological action: yes

Components

Name UniProt ID Details
Transferrin receptor 1 Q9UP52 Details
Transferrin receptor 2 P02786 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

Comments
Drug created on November 18, 2007 11:22 / Updated on November 30, 2013 11:02