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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
ZOLNot AvailableNot Available
Zoledronic acidNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
AclastaNovartis Pharmaceuticals
Reclast Novartis
ZometaNovartis
Zometa ConcentrateNovartis Pharmaceuticals
Brand mixturesNot 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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassAzoles
SubclassImidazoles
Direct parentN-substituted Imidazoles
Alternative parentsOrganic Phosphonic Acids; Polyamines
Substituentsphosphonic acid; phosphonic acid derivative; polyamine; amine; organonitrogen compound
Classification descriptionThis compound belongs to the n-substituted imidazoles. These are heterocyclic compounds containing an imidazole ring substituted at position 1.
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
Property Value Probability
Human Intestinal Absorption - 0.9723
Blood Brain Barrier + 0.825
Caco-2 permeable - 0.6418
P-glycoprotein substrate Non-substrate 0.5602
P-glycoprotein inhibitor I Non-inhibitor 0.943
P-glycoprotein inhibitor II Non-inhibitor 0.9961
Renal organic cation transporter Non-inhibitor 0.9366
CYP450 2C9 substrate Non-substrate 0.8319
CYP450 2D6 substrate Non-substrate 0.8201
CYP450 3A4 substrate Non-substrate 0.7551
CYP450 1A2 substrate Non-inhibitor 0.8531
CYP450 2C9 substrate Non-inhibitor 0.8576
CYP450 2D6 substrate Non-inhibitor 0.8935
CYP450 2C19 substrate Non-inhibitor 0.8319
CYP450 3A4 substrate Non-inhibitor 0.9334
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9904
Ames test Non AMES toxic 0.5596
Carcinogenicity Non-carcinogens 0.8194
Biodegradation Not ready biodegradable 0.5431
Rat acute toxicity 2.3342 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.8515
hERG inhibition (predictor II) Non-inhibitor 0.8616
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
Packagers
Dosage forms
FormRouteStrength
Injection, solutionIntravenous0.05 mg/ml
Injection, solution, concentrateIntravenous0.8 mg/ml
Prices
Unit descriptionCostUnit
Zometa 4 mg/5ml Concentrate 5ml Vial1095.69USDvial
Reclast 5 mg/100ml Solution13.39USDml
Reclast 5 mg/100 ml solution12.88USDml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States49391301993-03-022013-03-02
Canada13389371997-02-252014-02-25
Canada13388951997-02-042014-02-04
Properties
Statesolid
Experimental Properties
PropertyValueSource
water solubilitySparingly solubleNot Available
logP-4.2Not Available
Predicted Properties
PropertyValueSource
water solubility3.27e+00 g/lALOGPS
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 area153.11ChemAxon
rotatable bond count4ChemAxon
refractivity52.16ChemAxon
polarizability20.1ChemAxon
number of rings1ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
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
ResourceLink
KEGG DrugD01968
PubChem Compound68740
PubChem Substance46507310
ChemSpider61986
BindingDB12578
Therapeutic Targets DatabaseDAP001539
PharmGKBPA10235
HETZOL
Drug Product Database2242725
RxListhttp://www.rxlist.com/cgi/generic/zometa.htm
WikipediaZoledronate
ATC CodesM05BA08
AHFS Codes
  • 92:00.00
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(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

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