Gallium nitrate - DrugBank

ID Pharmacology Interactions References Trials Economics Properties Spectra Taxonomy

Targets (6)Carriers (1)Transporters (1)

Targets (6)Carriers (1)Transporters (1)Biointeractions (4)

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

MOL SDF PDB SMILES InChI

Synonyms

Gallium nitrate (anhydrous)

Nitric acid, gallium salt, anhydrate

External IDs

Not Available

Product Ingredients

Ingredient	UNII	CAS	InChI Key	Details
Gallium nitrate nonahydrate	VRA0C6810N	135886-70-3	VALBLFFHYPYRDR-UHFFFAOYSA-N	Details

Approved Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Ganite	Injection, solution, concentrate	25 mg/mL	Intravenous	Genta Incorporated	2003-09-17	2017-07-26	US

Approved Generic Prescription Products

Not Available

Approved Over the Counter Products

Not Available

Unapproved/Other Products

Not Available

International Brands

Not Available

Brand mixtures

Not Available

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

Symptomatic Hypercalcemia of malignancy

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.

Target	Kind	Pharmacological action	Actions	Organism	UniProt ID
Ribonucleoside-diphosphate reductase subunit M2	Protein	yes	inhibitor	Human	P31350	details
V-type proton ATPase subunit B, brain isoform	Protein	yes	inhibitor	Human	P21281	details
Osteocalcin	Protein	yes	antagonist	Human	P02818	details
Hydroxylapatite	Small molecule	yes	modulator	Human	not applicable	details
Protein-tyrosine-phosphatase	Protein	unknown	inhibitor	Shewanella sp.	Q9S427	details
Interleukin-1 beta	Protein	yes	antagonist	Human	P01584	details

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

Drug	Interaction	Drug group
Acetyldigitoxin	Acetyldigitoxin may decrease the cardiotoxic activities of Gallium nitrate.	Approved
BCG vaccine	The therapeutic efficacy of Bcg can be decreased when used in combination with Gallium nitrate.	Investigational
Bevacizumab	Bevacizumab may increase the cardiotoxic activities of Gallium nitrate.	Approved, Investigational
Cabazitaxel	The risk or severity of adverse effects can be increased when Cabazitaxel is combined with Gallium nitrate.	Approved
Cyclophosphamide	Cyclophosphamide may increase the cardiotoxic activities of Gallium nitrate.	Approved, Investigational
Denosumab	The risk or severity of adverse effects can be increased when Denosumab is combined with Gallium nitrate.	Approved
Deslanoside	Deslanoside may decrease the cardiotoxic activities of Gallium nitrate.	Approved
Digitoxin	Digitoxin may decrease the cardiotoxic activities of Gallium nitrate.	Approved
Digoxin	Digoxin may decrease the cardiotoxic activities of Gallium nitrate.	Approved
Docetaxel	The risk or severity of adverse effects can be increased when Docetaxel is combined with Gallium nitrate.	Approved, Investigational
Fingolimod	Gallium nitrate may increase the immunosuppressive activities of Fingolimod.	Approved, Investigational
G17DT	The risk or severity of adverse effects can be increased when Gallium nitrate is combined with G17DT.	Investigational
GI-5005	The risk or severity of adverse effects can be increased when Gallium nitrate is combined with GI-5005.	Investigational
INGN 201	The risk or severity of adverse effects can be increased when Gallium nitrate is combined with INGN 201.	Investigational
INGN 225	The risk or severity of adverse effects can be increased when Gallium nitrate is combined with INGN 225.	Investigational
Leflunomide	The risk or severity of adverse effects can be increased when Gallium nitrate is combined with Leflunomide.	Approved, Investigational
Natalizumab	The risk or severity of adverse effects can be increased when Gallium nitrate is combined with Natalizumab.	Approved, Investigational
Oleandrin	Anvirzel may decrease the cardiotoxic activities of Gallium nitrate.	Experimental
Ouabain	Ouabain may decrease the cardiotoxic activities of Gallium nitrate.	Approved
Paclitaxel	The risk or severity of adverse effects can be increased when Paclitaxel is combined with Gallium nitrate.	Approved, Vet Approved
Pimecrolimus	The risk or severity of adverse effects can be increased when Pimecrolimus is combined with Gallium nitrate.	Approved, Investigational
Rabies virus inactivated antigen, A	The risk or severity of adverse effects can be increased when Gallium nitrate is combined with Rabies vaccine.	Approved
Rabies virus inactivated antigen, A	The therapeutic efficacy of Rabies vaccine can be decreased when used in combination with Gallium nitrate.	Approved
Rindopepimut	The risk or severity of adverse effects can be increased when Gallium nitrate is combined with CDX-110.	Investigational
Roflumilast	Roflumilast may increase the immunosuppressive activities of Gallium nitrate.	Approved
Sipuleucel-T	The therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Gallium nitrate.	Approved
SRP 299	The risk or severity of adverse effects can be increased when Gallium nitrate is combined with SRP 299.	Investigational
Tacrolimus	The risk or severity of adverse effects can be increased when Tacrolimus is combined with Gallium nitrate.	Approved, Investigational
TG4010	The risk or severity of adverse effects can be increased when Gallium nitrate is combined with TG4010.	Investigational
Tofacitinib	Gallium nitrate may increase the immunosuppressive activities of Tofacitinib.	Approved, Investigational
Trastuzumab	Trastuzumab may increase the cardiotoxic activities of Gallium nitrate.	Approved, Investigational

Food Interactions

Not Available

References

Synthesis Reference

Not Available

General References

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 ]
Leyland-Jones B: Treating cancer-related hypercalcemia with gallium nitrate. J Support Oncol. 2004 Nov-Dec;2(6):509-16. [PubMed:15605917 ]
Chitambar CR: Apoptotic mechanisms of gallium nitrate: basic and clinical investigations. Oncology (Williston Park). 2004 Nov;18(13 Suppl 10):39-44. [PubMed:15651176 ]
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

Resource	Link
Human Metabolome Database (HMDB)	HMDB15612
PubChem Compound	61635
PubChem Substance	46508923
ChemSpider	55543
ChEMBL	CHEMBL1200983
Therapeutic Targets Database	DAP001096
PharmGKB	PA164781198
Drugs.com	http://www.drugs.com/cdi/gallium.html

ATC Codes

Not Available

AHFS Codes

Not Available

PDB Entries

Not Available

FDA label

Not Available

MSDS

Download (8.19 KB)

Clinical Trials

Phase	Status	Purpose	Conditions	Count
1	Active Not Recruiting	Other	Cystic Fibrosis (CF)	1
1	Completed	Treatment	Brain and Central Nervous System Tumors / Malignant Lymphomas / Neuroblastomas / Sarcomas / Unspecified Childhood Solid Tumor, Protocol Specific	1
2	Completed	Treatment	Lymphoma, Intermediate-Grade / Lymphoma, Low-Grade / Non-Hodgkin's Lymphoma (NHL) / Refractory Lymphomas / Relapsed Lymphomas	1
2	Completed	Treatment	Malignant Lymphomas	1
2	Recruiting	Treatment	Cystic Fibrosis (CF)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage forms

Form	Route	Strength
Injection, solution, concentrate	Intravenous	25 mg/mL

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
logP	0.028	ChemAxon
pKa (Strongest Acidic)	-1.4	ChemAxon
pKa (Strongest Basic)	-6.1	ChemAxon
Physiological Charge	-1	ChemAxon
Hydrogen Acceptor Count	3	ChemAxon
Hydrogen Donor Count	0	ChemAxon
Polar Surface Area	68.88 Å²	ChemAxon
Rotatable Bond Count	0	ChemAxon
Refractivity	9.85 m³·mol^-1	ChemAxon
Polarizability	3.24 Å³	ChemAxon
Number of Rings	0	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	No	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon

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 inhibitor	Non-inhibitor	0.8894
CYP450 2D6 inhibitor	Non-inhibitor	0.9223
CYP450 2C19 inhibitor	Non-inhibitor	0.8364
CYP450 3A4 inhibitor	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

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 chemical entities 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

Chemical entities

Super Class

Inorganic compounds

Class

Mixed metal/non-metal compounds

Sub Class

Post-transition metal oxoanionic compounds

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

Details

1. Ribonucleoside-diphosphate reductase subunit M2

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

Chitambar CR: Apoptotic mechanisms of gallium nitrate: basic and clinical investigations. Oncology (Williston Park). 2004 Nov;18(13 Suppl 10):39-44. [PubMed:15651176 ]
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 ]
Straus DJ: Gallium nitrate in the treatment of lymphoma. Semin Oncol. 2003 Apr;30(2 Suppl 5):25-33. [PubMed:12776257 ]

Details

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

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

Bockman R: The effects of gallium nitrate on bone resorption. Semin Oncol. 2003 Apr;30(2 Suppl 5):5-12. [PubMed:12776254 ]
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 ]
Jakupec MA, Keppler BK: Gallium and other main group metal compounds as antitumor agents. Met Ions Biol Syst. 2004;42:425-62. [PubMed:15206110 ]

Details

3. Osteocalcin

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

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 ]
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 ]

Details

4. Hydroxylapatite

Kind: Small molecule
Organism: Human
Pharmacological action: yes
Actions: modulator

References

Bockman R: The effects of gallium nitrate on bone resorption. Semin Oncol. 2003 Apr;30(2 Suppl 5):5-12. [PubMed:12776254 ]

Details

5. Protein-tyrosine-phosphatase

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

Chitambar CR: Apoptotic mechanisms of gallium nitrate: basic and clinical investigations. Oncology (Williston Park). 2004 Nov;18(13 Suppl 10):39-44. [PubMed:15651176 ]
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 ]
Straus DJ: Gallium nitrate in the treatment of lymphoma. Semin Oncol. 2003 Apr;30(2 Suppl 5):25-33. [PubMed:12776257 ]

Details

6. Interleukin-1 beta

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
Uniprot Name:: Interleukin-1 beta
Molecular Weight:: 30747.7 Da

References

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

Details

1. Serotransferrin

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
Uniprot Name:: Serotransferrin
Molecular Weight:: 77063.195 Da

References

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 ]
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 ]
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

Details

1. Transferrin receptor (Protein Group)

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:

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

References

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 September 01, 2017 11:24

Structure for DB05260 (Gallium nitrate)

Targets

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Carriers

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Transporters

Components:

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