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
- Weight
- Average: 255.738
Monoisotopic: 254.889034525 - Chemical Formula
- GaN3O9
- Synonyms
- Gallium nitrate (anhydrous)
- Gallium nitrate injection
- Nitric acid, gallium salt, anhydrate
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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- 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
Target Actions Organism URibonucleoside-diphosphate reductase subunit M2 inhibitorHumans UV-type proton ATPase subunit B, brain isoform inhibitorHumans - 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 Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareMagnesium The 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
Ingredient UNII CAS InChI Key Gallium nitrate nonahydrate VRA0C6810N 135886-70-3 GOMSPTBXILHTSG-UHFFFAOYSA-N - Active Moieties
Name Kind UNII CAS InChI Key Gallium cation ionic F7K5MP217W 22537-33-3 CKHJYUSOUQDYEN-UHFFFAOYSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Ganite Injection, solution, concentrate 25 mg/1mL Intravenous Genta Incorporated 2003-09-17 Not applicable US
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
- 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]
- 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]
- 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]
- 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]
- Bockman R: The effects of gallium nitrate on bone resorption. Semin Oncol. 2003 Apr;30(2 Suppl 5):5-12. [Article]
- 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]
- 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]
- Santa Cruz Biotechnology: Gallium(III) nitrate hydrate MSDS [Link]
- DailyMed Label: GANITE (gallium nitrate) Intravenous Injection [Link]
- 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]
- External Links
- Human Metabolome Database
- HMDB0015612
- PubChem Compound
- 61635
- PubChem Substance
- 46508923
- ChemSpider
- 55543
- 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 Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 2 Completed Treatment Cystic Fibrosis (CF) 1 2 Completed Treatment Low Grade Lymphoma / Lymphoma, Intermediate-Grade / Non-Hodgkin's Lymphoma (NHL) / Non-Hodgkin's Lymphomas / Refractory Lymphomas / Relapsed Lymphomas 1 2 Completed Treatment Lymphoma 1 1 Completed Other Cystic Fibrosis (CF) 1 1 Completed Treatment Brain and Central Nervous System Tumors / Lymphoma / Neuroblastoma (NB) / Sarcomas / Unspecified Childhood Solid Tumor, Protocol Specific 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution, concentrate Intravenous 25 mg/1mL - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Liquid
- Experimental Properties
Property Value Source boiling point (°C) 85 https://www.fishersci.com/store/msds?partNumber=AA4348418&productDescription=GALL+III+NRATE+SOL+GA+9-10+50G&vendorId=VN00024248&countryCode=US&language=en - Predicted Properties
Property Value Source logP -2.6 Chemaxon pKa (Strongest Basic) -9.9 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 3 Chemaxon Hydrogen Donor Count 0 Chemaxon Polar Surface Area 66.2 Å2 Chemaxon Rotatable Bond Count 0 Chemaxon Refractivity 8.35 m3·mol-1 Chemaxon Polarizability 3.28 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
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Not Available
- Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Targets
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
- 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
- Chitambar CR: Apoptotic mechanisms of gallium nitrate: basic and clinical investigations. Oncology (Williston Park). 2004 Nov;18(13 Suppl 10):39-44. [Article]
- 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]
- Straus DJ: Gallium nitrate in the treatment of lymphoma. Semin Oncol. 2003 Apr;30(2 Suppl 5):25-33. [Article]
- 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]
- 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
Carriers
- 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
- 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]
- 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]
- 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]
- Chitambar CR: Apoptotic mechanisms of gallium nitrate: basic and clinical investigations. Oncology (Williston Park). 2004 Nov;18(13 Suppl 10):39-44. [Article]
- 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