NAV

Gallium nitrate

Identification

Summary

Gallium nitrate is a drug previously indicated to treat cancer-related hypercalcemia.

Brand Names
Ganite
Generic Name
Gallium nitrate
DrugBank Accession Number
DB05260
Background

Gallium nitrate is a nitrate salt of Gallium cation, a heavy metal that has been used as a diagnostic agent.4 Gallium nitrate is reported to possess antiresorptive and hypocalcemic effects on bone.5 GANITE, a product of gallium nitrate previously used to treat cancer-related hypercalcemia, was discontinued from marketing in the US for reasons other than safety or effectiveness.10

Apart from cancer-related hypercalcemia, gallium nitrate has been studied in arthritis, autoimmune disorders, and tumours.7

Type
Small Molecule
Groups
Approved, Investigational
Structure
Similar Structures
Weight
Average: 255.738
Monoisotopic: 254.889034525
Chemical Formula
GaN3O9
Synonyms
  • Gallium nitrate (anhydrous)
  • Gallium nitrate injection
  • Nitric acid, gallium salt, anhydrate
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Pharmacology

Indication

Gallium nitrate does not currently have approved indications. It was previously used in the treatment of cancer-related hypercalcemia.9

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Gallium nitrate produces a hypocalcemic effect by inhibiting calcium resorption from bone, possibly blocking osteoclast activity and reducing increased bone turnover.9 Preclinical studies demonstrated that gallium dose-dependently accumulates in areas of high bone turnover, where it is incorporated into hydroxyapatite, making it less susceptible to dissolution and osteoclast-mediated resorption.4,5 No cytotoxic effects were observed on bone cells in drug-treated animals.9

Gallium nitrate exhibits antitumour activity, which is reported to be unrelated to the physiological mechanism involved in its bone turnover effects.4 Anti-inflammatory and immunosuppressant effects have also been documented.7

Mechanism of action

A high incidence of hypercalcemia is often observed in patients with non-small cell lung cancer, breast cancer, multiple myeloma, kidney cancer, and cancer of head and neck. Hypercalcemia of malignancy seems to result from an imbalance between the net resorption of bone and urinary excretion of calcium. Patients with extensive osteolytic bone metastases frequently develop hypercalcemia.9 Although in vitro and animal studies have been performed to investigate the mechanism of action of gallium nitrate, the precise mechanism for inhibiting calcium resorption has not been determined.9 Gallium, the active component that exerts the physiological effects of gallium nitrate, may induce physicochemical changes in the bone matrix to promote hydroxyapatite crystallization and attenuate mineral dissolution.4,5 Gallium may also decrease acid secretion by osteoclasts 5 and modulate the synthesis of osteocalcin, an osteoblast-specific bone matrix protein that triggers bone resorption.6 Osteoclast morphology or viability is not reported to be affected.4

Gallium nitrate may modulate inflammation. In vitro, it was shown to block the production of inflammatory cytokines, such as interleukin-1 (IL-1) beta, by macrophage-like cells. Gallium nitrate also dose-dependently inhibited matrix metalloproteinase activity promoted by tissue plasminogen activator (tPA).1,2

TargetActionsOrganism
URibonucleoside-diphosphate reductase subunit M2
inhibitor
Humans
UV-type proton ATPase subunit B, brain isoform
inhibitor
Humans
Absorption

Gallium nitrate was infused at a daily dose of 200 mg/m2 for 5 (n=2) or 7 (n=10) consecutive days to 12 cancer patients. In most patients, mean steady-state plasma concentrations were reached after 18 to 24 hours of infusion. The average steady-state plasma levels of gallium observed among seven fully evaluable patients was between 1134 and 2399 ng/mL. In one patient who received daily infusion doses of 100, 150 and 200 mg/m2, the apparent steady-state levels of gallium did not increase proportionally with an increase in dose.9

Volume of distribution

In phase I studies involving cancer patients who received a short-term intravenous infusion of single doses ranging from 300 to 900 mg/m2, the mean volume of distribution of gallium was 1.27 L/kg.4

Protein binding

No information is available.

Metabolism

Gallium nitrate is not metabolized either by the liver or the kidney.9

Route of elimination

Gallium nitrate appears to be significantly excreted via the kidney.3,9 In phase I studies involving cancer patients who received a short-term intravenous infusion of single doses ranging from 300 to 900 mg/m2, about two-thirds of the administered dose was recovered in the urine in the first 24 hours post-dose.4

Half-life

In phase I studies involving cancer patients who received a short-term intravenous infusion of single doses ranging from 300 to 900 mg/m2, a biphasic curve was observed. Gallium nitrate exhibited a mean initial (distribution phase) half-life of 1 to 1.5 hours and a terminal (elimination phase) half-lives of 25 to 30 hours.4

Clearance

In cancer patients who received a daily infusion of gallium nitrate at a dose of 200 mg/m2 for five to seven consecutive days, the average plasma clearance of gallium was 0.15 L/hr/kg (range: 0.12 to 0.20 L/hr/kg).9

Adverse Effects
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Toxicity

The oral, subcutaneous, and intravenous LD50 in mice are 4360 mg/kg, 600 mg/kg, and 55 mg/kg, respectively.8

Rapid intravenous infusion of gallium nitrate or use of doses higher than recommended (200 mg/m2) may cause nausea and vomiting and a substantially increased risk of renal insufficiency. In the event of overdosage, further drug administration should be discontinued, serum calcium should be monitored, and the patient should receive vigorous intravenous hydration, with or without diuretics, for two to three days. During this time period, renal function and urinary output should be carefully monitored so that fluid intake and output are balanced.9

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
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MagnesiumThe serum concentration of Magnesium can be decreased when it is combined with Gallium nitrate.
Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Gallium nitrate nonahydrateVRA0C6810N135886-70-3GOMSPTBXILHTSG-UHFFFAOYSA-N
Active Moieties
NameKindUNIICASInChI Key
Gallium cationionicF7K5MP217W22537-33-3CKHJYUSOUQDYEN-UHFFFAOYSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
GaniteInjection, solution, concentrate25 mg/1mLIntravenousGenta Incorporated2003-09-17Not applicableUS flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
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
Inorganic oxide / Inorganic post-transition metal salt / Inorganic salt / Post-transition metal nitrate
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
Y2V2R4W9TQ
CAS number
13494-90-1
InChI Key
CHPZKNULDCNCBW-UHFFFAOYSA-N
InChI
InChI=1S/Ga.3NO3/c;3*2-1(3)4/q+3;3*-1
IUPAC Name
gallium(3+) trinitrate
SMILES
[Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O

References

General 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. [Article]
  2. Panagakos FS, Kumar E, Venescar C, Guidon P: The effect of gallium nitrate on synoviocyte MMP activity. Biochimie. 2000 Feb;82(2):147-51. doi: 10.1016/s0300-9084(00)00384-9. [Article]
  3. Kelsen DP, Alcock N, Yeh S, Brown J, Young C: Pharmacokinetics of gallium nitrate in man. Cancer. 1980 Nov 1;46(9):2009-13. doi: 10.1002/1097-0142(19801101)46:9<2009::aid-cncr2820460919>3.0.co;2-a. [Article]
  4. Todd PA, Fitton A: Gallium nitrate. A review of its pharmacological properties and therapeutic potential in cancer related hypercalcaemia. Drugs. 1991 Aug;42(2):261-73. doi: 10.2165/00003495-199142020-00007. [Article]
  5. Bockman R: The effects of gallium nitrate on bone resorption. Semin Oncol. 2003 Apr;30(2 Suppl 5):5-12. [Article]
  6. Bockman RS, Guidon PT Jr, Pan LC, Salvatori R, Kawaguchi A: Gallium nitrate increases type I collagen and fibronectin mRNA and collagen protein levels in bone and fibroblast cells. J Cell Biochem. 1993 Aug;52(4):396-403. doi: 10.1002/jcb.240520404. [Article]
  7. Apseloff G: Therapeutic uses of gallium nitrate: past, present, and future. Am J Ther. 1999 Nov;6(6):327-39. doi: 10.1097/00045391-199911000-00008. [Article]
  8. Santa Cruz Biotechnology: Gallium(III) nitrate hydrate MSDS [Link]
  9. DailyMed Label: GANITE (gallium nitrate) Intravenous Injection [Link]
  10. The Federal Register: Determination That GANITE (Gallium Nitrate) Injectable and Five Other Drug Products Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness [Link]
Human Metabolome Database
HMDB0015612
PubChem Compound
61635
PubChem Substance
46508923
ChemSpider
55543
RxNav
25544
ChEMBL
CHEMBL1200983
Therapeutic Targets Database
DAP001096
PharmGKB
PA164781198
Drugs.com
Drugs.com Drug Page
Wikipedia
Gallium_nitrate
MSDS
Download (8.19 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentCystic Fibrosis (CF)1
2CompletedTreatmentLow Grade Lymphoma / Lymphoma, Intermediate-Grade / Non-Hodgkin's Lymphoma (NHL) / Refractory Lymphomas / Relapsed Lymphomas1
2CompletedTreatmentLymphoma1
1CompletedOtherCystic Fibrosis (CF)1
1CompletedTreatmentBrain and Central Nervous System Tumors / Lymphoma / Neuroblastoma (NB) / Sarcomas / Unspecified Childhood Solid Tumor, Protocol Specific1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solution, concentrateIntravenous25 mg/1mL
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
PropertyValueSource
boiling point (°C)85https://www.fishersci.com/store/msds?partNumber=AA4348418&productDescription=GALL+III+NRATE+SOL+GA+9-10+50G&vendorId=VN00024248&countryCode=US&language=en
Predicted Properties
PropertyValueSource
logP-2.6Chemaxon
pKa (Strongest Basic)-9.9Chemaxon
Physiological Charge-1Chemaxon
Hydrogen Acceptor Count3Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area66.2 Å2Chemaxon
Rotatable Bond Count0Chemaxon
Refractivity8.35 m3·mol-1Chemaxon
Polarizability3.28 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
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Targets

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Details1. Ribonucleoside-diphosphate reductase subunit M2
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Gallium, the active component of gallium nitrate, is reported to interact with this target.
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. [Article]
  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. [Article]
  3. Straus DJ: Gallium nitrate in the treatment of lymphoma. Semin Oncol. 2003 Apr;30(2 Suppl 5):25-33. [Article]
  4. Apseloff G: Therapeutic uses of gallium nitrate: past, present, and future. Am J Ther. 1999 Nov;6(6):327-39. doi: 10.1097/00045391-199911000-00008. [Article]
Details2. V-type proton ATPase subunit B, brain isoform
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Gallium, the active component of gallium nitrate, is reported to interact with this target.
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. [Article]
  2. Jakupec MA, Keppler BK: Gallium and other main group metal compounds as antitumor agents. Met Ions Biol Syst. 2004;42:425-62. [Article]

Carriers

Details1. Serotransferrin
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
Curator comments
Gallium cation binds to transferrin.
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. [Article]
  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. [Article]
  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. [Article]
  4. Chitambar CR: Apoptotic mechanisms of gallium nitrate: basic and clinical investigations. Oncology (Williston Park). 2004 Nov;18(13 Suppl 10):39-44. [Article]
  5. Apseloff G: Therapeutic uses of gallium nitrate: past, present, and future. Am J Ther. 1999 Nov;6(6):327-39. doi: 10.1097/00045391-199911000-00008. [Article]

Drug created at November 18, 2007 18:22 / Updated at September 28, 2023 05:46