Identification

Name
Gallium nitrate
Accession Number
DB05260
Type
Small Molecule
Groups
Approved, 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
Product Ingredients
IngredientUNIICASInChI Key
Gallium nitrate nonahydrateVRA0C6810N135886-70-3VALBLFFHYPYRDR-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
GaniteInjection, solution, concentrate25 mg/mLIntravenousGenta Incorporated2003-09-172017-07-26Us
Categories
UNII
Y2V2R4W9TQ
CAS number
13494-90-1
Weight
Average: 255.738
Monoisotopic: 254.889034525
Chemical Formula
GaN3O9
InChI Key
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

Pharmacology

Indication

For the treatment of hypercalcemia. Also intended for the treatment of non-hodgkin's lymphoma.

Structured Indications
Pharmacodynamics

Gallium 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 action

Gallium 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.

TargetActionsOrganism
ARibonucleoside-diphosphate reductase subunit M2
inhibitor
Human
AV-type proton ATPase subunit B, brain isoform
inhibitor
Human
AOsteocalcin
antagonist
Human
AHydroxylapatite
modulator
Human
UProtein-tyrosine-phosphatase
inhibitor
Shewanella sp.
AInterleukin-1 beta
antagonist
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination

Gallium nitrate is not metabolized either by the liver or the kidney and appears to be significantly excreted via the kidney.

Half life

Alpha: 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]
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Gallium nitrate.Approved
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Gallium nitrate.Experimental
BCG vaccineThe therapeutic efficacy of BCG vaccine can be decreased when used in combination with Gallium nitrate.Investigational
BevacizumabBevacizumab may increase the cardiotoxic activities of Gallium nitrate.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Gallium nitrate.Approved
Clostridium tetani toxoid antigen (formaldehyde inactivated)The therapeutic efficacy of Clostridium tetani toxoid antigen (formaldehyde inactivated) can be decreased when used in combination with Gallium nitrate.Approved
Corynebacterium diphtheriae toxoid antigen (formaldehyde inactivated)The therapeutic efficacy of Corynebacterium diphtheriae toxoid antigen (formaldehyde inactivated) can be decreased when used in combination with Gallium nitrate.Approved
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Gallium nitrate.Approved, Investigational
CymarinCymarin may decrease the cardiotoxic activities of Gallium nitrate.Experimental
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Gallium nitrate.Approved
DeslanosideDeslanoside may decrease the cardiotoxic activities of Gallium nitrate.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Gallium nitrate.Approved, Investigational
DigoxinDigoxin may decrease the cardiotoxic activities of Gallium nitrate.Approved
Digoxin Immune Fab (Ovine)Digoxin Immune Fab (Ovine) may decrease the cardiotoxic activities of Gallium nitrate.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Gallium nitrate.Approved, Investigational
FingolimodGallium nitrate may increase the immunosuppressive activities of Fingolimod.Approved, Investigational
G17DTThe therapeutic efficacy of G17DT can be decreased when used in combination with Gallium nitrate.Investigational
GI-5005The therapeutic efficacy of GI-5005 can be decreased when used in combination with Gallium nitrate.Investigational
GitoformateGitoformate may decrease the cardiotoxic activities of Gallium nitrate.Experimental
Hepatitis A VaccineThe therapeutic efficacy of Hepatitis A Vaccine can be decreased when used in combination with Gallium nitrate.Approved
Hepatitis B Vaccine (Recombinant)The therapeutic efficacy of Hepatitis B Vaccine (Recombinant) can be decreased when used in combination with Gallium nitrate.Approved, Withdrawn
INGN 201The therapeutic efficacy of INGN 201 can be decreased when used in combination with Gallium nitrate.Investigational
INGN 225The therapeutic efficacy of INGN 225 can be decreased when used in combination with Gallium nitrate.Investigational
Lanatoside CLanatoside C may decrease the cardiotoxic activities of Gallium nitrate.Experimental
LeflunomideThe risk or severity of adverse effects can be increased when Gallium nitrate is combined with Leflunomide.Approved, Investigational
MetildigoxinMetildigoxin may decrease the cardiotoxic activities of Gallium nitrate.Experimental
NatalizumabThe risk or severity of adverse effects can be increased when Gallium nitrate is combined with Natalizumab.Approved, Investigational
OleandrinOleandrin may decrease the cardiotoxic activities of Gallium nitrate.Experimental, Investigational
OuabainOuabain may decrease the cardiotoxic activities of Gallium nitrate.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Gallium nitrate.Approved, Vet Approved
PeruvosidePeruvoside may decrease the cardiotoxic activities of Gallium nitrate.Experimental
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Gallium nitrate.Approved, Investigational
ProscillaridinProscillaridin may decrease the cardiotoxic activities of Gallium nitrate.Experimental
Rabies virus inactivated antigen, AThe risk or severity of adverse effects can be increased when Gallium nitrate is combined with Rabies virus inactivated antigen, A.Approved
Rabies virus inactivated antigen, AThe therapeutic efficacy of Rabies virus inactivated antigen, A can be decreased when used in combination with Gallium nitrate.Approved
RindopepimutThe therapeutic efficacy of Rindopepimut can be decreased when used in combination with Gallium nitrate.Investigational
RoflumilastRoflumilast may increase the immunosuppressive activities of Gallium nitrate.Approved
Rotavirus VaccineThe therapeutic efficacy of Rotavirus Vaccine can be decreased when used in combination with Gallium nitrate.Approved
Rubella virus vaccineThe therapeutic efficacy of Rubella virus vaccine can be decreased when used in combination with Gallium nitrate.Approved
Salmonella typhi ty21a live antigenThe therapeutic efficacy of Salmonella typhi ty21a live antigen can be decreased when used in combination with Gallium nitrate.Approved
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Gallium nitrate.Approved
SRP 299The therapeutic efficacy of SRP 299 can be decreased when used in combination with Gallium nitrate.Investigational
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Gallium nitrate.Approved, Investigational
TecemotideThe therapeutic efficacy of Tecemotide can be decreased when used in combination with Gallium nitrate.Investigational
TG4010The therapeutic efficacy of TG4010 can be decreased when used in combination with Gallium nitrate.Investigational
TofacitinibGallium nitrate may increase the immunosuppressive activities of Tofacitinib.Approved, Investigational
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Gallium nitrate.Approved, Investigational
Yellow fever vaccineThe therapeutic efficacy of Yellow fever vaccine can be decreased when used in combination with Gallium nitrate.Approved
Zoster vaccineThe therapeutic efficacy of Zoster vaccine can be decreased when used in combination with Gallium nitrate.Approved
Food Interactions
Not Available

References

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
Human Metabolome Database
HMDB15612
PubChem Compound
61635
PubChem Substance
46508923
ChemSpider
55543
ChEMBL
CHEMBL1200983
Therapeutic Targets Database
DAP001096
PharmGKB
PA164781198
Drugs.com
Drugs.com Drug Page
MSDS
Download (8.19 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingOtherCystic Fibrosis (CF)1
1CompletedTreatmentBrain and Central Nervous System Tumors / Malignant Lymphomas / Neuroblastomas / Sarcomas / Unspecified Childhood Solid Tumor, Protocol Specific1
2CompletedTreatmentLymphoma, Intermediate-Grade / Lymphoma, Low-Grade / Non-Hodgkin's Lymphoma (NHL) / Refractory Lymphomas / Relapsed Lymphomas1
2CompletedTreatmentMalignant Lymphomas1
2RecruitingTreatmentCystic Fibrosis (CF)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solution, concentrateIntravenous25 mg/mL
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not 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 FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Description
This 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.
Kingdom
Inorganic compounds
Super Class
Mixed metal/non-metal compounds
Class
Post-transition metal oxoanionic compounds
Sub Class
Post-transition metal nitrates
Direct Parent
Post-transition metal nitrates
Alternative Parents
Post-transition metal salts / Inorganic salts / Inorganic oxides
Substituents
Post-transition metal nitrate / Inorganic post-transition metal salt / Inorganic oxide / Inorganic salt
Molecular Framework
Not Available
External Descriptors
Not 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
Uniprot Name
Ribonucleoside-diphosphate reductase subunit M2
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
Uniprot Name
V-type proton ATPase subunit B, brain isoform
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
Uniprot Name
Osteocalcin
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
Uniprot Name
Protein-tyrosine-phosphatase
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, ...
Gene Name
IL1B
Uniprot ID
P01584
Uniprot Name
Interleukin-1 beta
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 si...
Gene Name
TF
Uniprot ID
P02787
Uniprot Name
Serotransferrin
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 apotransferri...

Components:
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]

Drug created on November 18, 2007 11:22 / Updated on November 09, 2017 03:50