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Identification
NameZoledronate
Accession NumberDB00399  (APRD01294, DB06286)
TypeSmall Molecule
GroupsApproved
Description

Zoledronate (zoledronic acid, marketed by Novartis under the trade names Zometa and Reclast) is a bisphosphonate. Zometa is used to prevent skeletal fractures in patients with cancers such as multiple myeloma and prostate cancer. It can also be used to treat hypercalcemia of malignancy and can be helpful for treating pain from bone metastases.

An annual dose of Zoledronate may also prevent recurring fractures in patients with a previous hip fracture.

Zoledronate is a single 5 mg infusion for the treatment of Paget’s disease of bone. In 2007, the FDA also approved Reclast for the treatment of postmenopausal osteoporosis.

Structure
Thumb
Synonyms
SynonymLanguageCode
(1-Hydroxy-2-(1H-imidazol-1-yl)ethylidene)bisphosphonic acidNot AvailableNot Available
(1-Hydroxy-2-imidazol-1-ylethylidene)diphosphonic acidNot AvailableNot Available
ReclastNot AvailableNot Available
ZOLNot AvailableNot Available
Zoledronic acidNot AvailableNot Available
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Zometainjection, solution, concentrate4 mg/5mLintravenousNovartis Pharmaceuticals Corporation2001-08-20Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Reclastinjection, solution5 mg/100mLintravenousNovartis Pharmaceuticals Corporation2007-04-01Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zometainjection, solution, concentrate4 mg/100mLintravenousNovartis Pharmaceuticals Corporation2001-08-20Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic Acidinjection, solution.04 mg/mLintravenousSagent Pharmaceuticals2013-03-02Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Aclastasolution5 mgintravenousNovartis Pharmaceuticals Canada IncNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Zoledronic Acidinjection, solution, concentrate4 mg/5mLintravenousWest ward Pharmaceutical Corp2013-06-03Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic Acidsolution5 mg/100mLintravenousAkorn, Inc.2014-08-21Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic Acidinjection, solution, concentrate4 mg/5mLintravenousAkorn2014-05-22Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic Acidinjection, solution4 mg/5mLintravenousHeritage Pharmaceuticals Inc.2012-12-20Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic Acidinjection, solution5 mg/100mLintravenousHeritage Pharmaceuticals Inc.2012-12-20Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic Acidinjection, solution, concentrate.8 mg/mLintravenousSagent Pharmaceuticals2014-12-29Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic Acidinjection, solution.05 mg/mLintravenousSagent Pharmaceuticals2013-03-02Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic Acidinjection, solution, concentrate4 mg/5mLintravenousPar Pharmaceutical Companies, Inc.2013-03-04Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic Acidinjection, solution5 mg/100mLintravenousPar Pharmaceutical Companies, Inc.2013-08-05Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic Acidinjection, solution, concentrate4 mg/5mLintravenousJHP Pharmaceuticals, LLC.2013-05-07Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic Acidinjection, solution, concentrate4 mg/5mLintravenousDr. Reddy's Laboratories Inc.2013-08-19Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic Acidinjection, solution5 mg/100mLintravenousDr.Reddy's Laboratories Inc2013-08-19Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic Acidinjection, solution, concentrate4 mg/5mLintravenousActavis Pharma, Inc.2015-01-05Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic Acidinjection, solution, concentrate4 mg/5mLintravenousSun Pharma Global FZE2013-03-04Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic AcidkitSun Pharma Global FZE2013-03-04Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic Acidinjection, solution, concentrate4 mg/5mLintravenousAmneal Agila, Llc2012-04-23Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic Acidinjection, solution, concentrate4 mg/5mLintravenousDr. Reddy's Laboratories Limited2013-03-04Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic Acidinjection, solution5 mg/100mLintravenousDr.Reddy's Laboratories Ltd2013-04-03Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic Acidinjection, solution5 mg/100mLintravenousWockhardt Limited2013-03-02Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic Acidinjection4 mg/5mLintravenousWockhardt Limited2013-03-02Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic Acidinjection, solution, concentrate4 mg/5mLintravenousApotex Corp2013-09-20Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic Acidinjection4 mg/5mLintravenousFresenius Kabi USA, LLC2014-09-04Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic Acidinjection, solution5 mg/100mLintravenousWockhardt USA LLC.2013-03-02Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic Acidinjection4 mg/5mLintravenousWockhardt USA LLC.2013-03-02Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronic Acidinjection, solution, concentrate4 mg/5mLintravenousMylan Institutional LLC2013-03-05Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zoledronicinjection4 mg/5mLintravenousGland Pharma Limited2013-09-20Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Over the Counter ProductsNot Available
International Brands
NameCompany
Zometa ConcentrateNovartis Pharmaceuticals
Brand mixturesNot Available
SaltsNot Available
Categories
CAS number118072-93-8
WeightAverage: 272.0896
Monoisotopic: 271.996323708
Chemical FormulaC5H10N2O7P2
InChI KeyXRASPMIURGNCCH-UHFFFAOYSA-N
InChI
InChI=1S/C5H10N2O7P2/c8-5(15(9,10)11,16(12,13)14)3-7-2-1-6-4-7/h1-2,4,8H,3H2,(H2,9,10,11)(H2,12,13,14)
IUPAC Name
[1-hydroxy-2-(1H-imidazol-1-yl)-1-phosphonoethyl]phosphonic acid
SMILES
OC(CN1C=CN=C1)(P(O)(O)=O)P(O)(O)=O
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as bisphosphonates. These are organic compounds containing two phosphonate groups linked together through a carbon atoms.
KingdomOrganic compounds
Super ClassOrganophosphorus compounds
ClassOrganic phosphonic acids and derivatives
Sub ClassBisphosphonates
Direct ParentBisphosphonates
Alternative Parents
Substituents
  • Bisphosphonate
  • N-substituted imidazole
  • Heteroaromatic compound
  • Organophosphonic acid
  • Imidazole
  • Azole
  • Azacycle
  • Organoheterocyclic compound
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Pharmacology
IndicationFor the treatment of hypercalcemia of malignancy. Also for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. In May of 2007, the drug was approved for treatment of Paget’s Disease.
PharmacodynamicsZoledronate is a bisphosphonic acid which is an inhibitor of osteoclastic bone resorption. Zoledronate is used to prevent osteoporosis and skeletal fractures, particularly in patients with cancers such as multiple myeloma and prostate cancer. It can also be used to treat hypercalcemia, particularly hypercalcemia of malignancy. It can also be helpful for treating pain from bone metastases.
Mechanism of actionThe action of zoledronate on bone tissue is based partly on its affinity for hydroxyapatite, which is part of the mineral matrix of bone. Zoledronate also targets farnesyl pyrophosphate (FPP) synthase. Nitrogen-containing bisphosphonates such as zoledronate appear to act as analogues of isoprenoid diphosphate lipids, thereby inhibiting FPP synthase, an enzyme in the mevalonate pathway. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and GGPP) that are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins. This activity inhibits osteoclast activity and reduces bone resorption and turnover. In postmenopausal women, it reduces the elevated rate of bone turnover, leading to, on average, a net gain in bone mass.
AbsorptionPoorly absorbed (oral absorption is about 1% of what intravenous absorption is).
Volume of distributionNot Available
Protein bindingApproximately 22% bound in human plasma, independent of the concentration. However, Canadian product information states binding to human plasma protein is approximately 56%.
Metabolism

Zoledronate does not inhibit human P450 enzymes in vitro and does not undergo biotransformation in vivo.

Route of eliminationIn 64 patients with cancer and bone metastases, on average (± s.d.) 39 ± 16% of the administered zoledronic acid dose was recovered in the urine within 24 hours, with only trace amounts of drug found in urine post-Day 2.
Half life146 hours
Clearance
  • Renal cl=3.7 +/- 2.0 L/h
ToxicityThere is no experience of acute overdose. Two patients received zoledronate (32 mg) over 5 minutes in clinical trials. Neither patient experienced any clinical or laboratory toxicity. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Zoledronate Action PathwayDrug actionSMP00107
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.9723
Blood Brain Barrier+0.825
Caco-2 permeable-0.6418
P-glycoprotein substrateNon-substrate0.5602
P-glycoprotein inhibitor INon-inhibitor0.943
P-glycoprotein inhibitor IINon-inhibitor0.9961
Renal organic cation transporterNon-inhibitor0.9366
CYP450 2C9 substrateNon-substrate0.8319
CYP450 2D6 substrateNon-substrate0.8201
CYP450 3A4 substrateNon-substrate0.7551
CYP450 1A2 substrateNon-inhibitor0.8531
CYP450 2C9 substrateNon-inhibitor0.8576
CYP450 2D6 substrateNon-inhibitor0.8935
CYP450 2C19 substrateNon-inhibitor0.8319
CYP450 3A4 substrateNon-inhibitor0.9334
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9904
Ames testNon AMES toxic0.5596
CarcinogenicityNon-carcinogens0.8194
BiodegradationNot ready biodegradable0.5431
Rat acute toxicity2.3342 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8515
hERG inhibition (predictor II)Non-inhibitor0.8616
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
Packagers
Dosage forms
FormRouteStrength
Injectionintravenous4 mg/5mL
Injection, solutionintravenous.04 mg/mL
Injection, solutionintravenous.05 mg/mL
Injection, solutionintravenous4 mg/5mL
Injection, solutionintravenous5 mg/100mL
Injection, solution, concentrateintravenous.8 mg/mL
Injection, solution, concentrateintravenous4 mg/100mL
Injection, solution, concentrateintravenous4 mg/5mL
Kit
Solutionintravenous5 mg
Solutionintravenous5 mg/100mL
Prices
Unit descriptionCostUnit
Zometa 4 mg/5ml Concentrate 5ml Vial1095.69USD vial
Reclast 5 mg/100ml Solution13.39USD ml
Reclast 5 mg/100 ml solution12.88USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
Canada13388951997-02-042014-02-04
Canada13389371997-02-252014-02-25
United States49391301993-03-022013-03-02
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubilitySparingly solubleNot Available
logP-4.2Not Available
Predicted Properties
PropertyValueSource
Water Solubility3.27 mg/mLALOGPS
logP-0.93ALOGPS
logP-3.9ChemAxon
logS-1.9ALOGPS
pKa (Strongest Acidic)0.66ChemAxon
pKa (Strongest Basic)6.67ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area153.11 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity52.16 m3·mol-1ChemAxon
Polarizability20.1 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Judith Aronhime, Revital Lifshitz-Liron, “Zoledronic acid crystal forms, zoledronate sodium salt crystal forms, amorphous zoledronate sodium salt, and processes for their preparation.” U.S. Patent US20050054616, issued March 10, 2005.

US20050054616
General Reference
  1. Lyles KW, Colon-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen EF, Boonen S: Zoledronic Acid and Clinical Fractures and Mortality after Hip Fracture. N Engl J Med. 2007 Sep 26;. Pubmed
  2. Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P, Trechsel U, Widmer A, Devogelaer JP, Kaufman JM, Jaeger P, Body JJ, Brandi ML, Broell J, Di Micco R, Genazzani AR, Felsenberg D, Happ J, Hooper MJ, Ittner J, Leb G, Mallmin H, Murray T, Ortolani S, Rubinacci A, Saaf M, Samsioe G, Verbruggen L, Meunier PJ: Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med. 2002 Feb 28;346(9):653-61. Pubmed
  3. Durie BG, Katz M, Crowley J: Osteonecrosis of the jaw and bisphosphonates. N Engl J Med. 2005 Jul 7;353(1):99-102; discussion 99-102. Pubmed
External Links
ATC CodesM05BA08
AHFS Codes
  • 92:00.00
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (57.9 KB)
Interactions
Drug InteractionsSearched, but no interactions found.
Food InteractionsNot Available

Targets

1. Farnesyl pyrophosphate synthase

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Farnesyl pyrophosphate synthase P14324 Details

References:

  1. Dunford JE, Thompson K, Coxon FP, Luckman SP, Hahn FM, Poulter CD, Ebetino FH, Rogers MJ: Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther. 2001 Feb;296(2):235-42. Pubmed
  2. Glickman JF, Schmid A: Farnesyl pyrophosphate synthase: real-time kinetics and inhibition by nitrogen-containing bisphosphonates in a scintillation assay. Assay Drug Dev Technol. 2007 Apr;5(2):205-14. Pubmed
  3. Guo RT, Cao R, Liang PH, Ko TP, Chang TH, Hudock MP, Jeng WY, Chen CK, Zhang Y, Song Y, Kuo CJ, Yin F, Oldfield E, Wang AH: Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10022-7. Epub 2007 May 29. Pubmed
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Geranylgeranyl pyrophosphate synthase

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Geranylgeranyl pyrophosphate synthase O95749 Details

References:

  1. Guo RT, Cao R, Liang PH, Ko TP, Chang TH, Hudock MP, Jeng WY, Chen CK, Zhang Y, Song Y, Kuo CJ, Yin F, Oldfield E, Wang AH: Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10022-7. Epub 2007 May 29. Pubmed

3. Hydroxylapatite

Kind: small molecule

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details

References:

  1. Jahnke W, Henry C: An in vitro assay to measure targeted drug delivery to bone mineral. ChemMedChem. 2010 May 3;5(5):770-6. Pubmed
  2. Nancollas GH, Tang R, Phipps RJ, Henneman Z, Gulde S, Wu W, Mangood A, Russell RG, Ebetino FH: Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone. 2006 May;38(5):617-27. Epub 2005 Jul 20. Pubmed

Transporters

1. Multidrug resistance-associated protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Multidrug resistance-associated protein 1 P33527 Details

References:

  1. Yildiz M, Celik-Ozenci C, Akan S, Akan I, Sati L, Demir R, Savas B, Ozben T, Samur M, Ozdogan M, Artac M, Bozcuk H: Zoledronic acid is synergic with vinblastine to induce apoptosis in a multidrug resistance protein-1 dependent way: an in vitro study. Cell Biol Int. 2006 Mar;30(3):278-82. Epub 2006 Feb 2. Pubmed

Comments
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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:10