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Identification
Name Zoledronate
Accession Number DB00399 (APRD01294, DB06286)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
ZOL
Zoledronic acid
Salts Not Available
Brand names
Name Company
Aclasta Novartis Pharmaceuticals
Reclast Novartis
Zometa Novartis
Zometa Concentrate Novartis Pharmaceuticals
Brand mixtures Not Available
Categories
  • Antihypocalcemic Agents
  • Bisphosphonates
  • Antiresorptives
  • Bone Density Conservation Agents
CAS number 118072-93-8
Weight Average: 272.0896
Monoisotopic: 271.996323708
Chemical Formula C5H10N2O7P2
InChI Key InChIKey=XRASPMIURGNCCH-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)
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Bisphosphonates
Substructures
  • Hydroxy Compounds
  • Carboxylic Acids and Derivatives
  • Phosphonic Acids and Derivatives
  • Imidazoles
  • Heterocyclic compounds
  • Aromatic compounds
  • Phosphinic Acids and Derivatives
  • Bisphosphonates
  • Cyanamides
Pharmacology
Indication For 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.
Pharmacodynamics Zoledronate 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 action The 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.
Absorption Poorly absorbed (oral absorption is about 1% of what intravenous absorption is).
Volume of distribution Not Available
Protein binding Approximately 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 elimination In 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 life 146 hours
Clearance
  • Renal cl=3.7 +/- 2.0 L/h
Toxicity There 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
Pathway Name SMPDB ID
Smp00107 Zoledronate Pathway SMP00107
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
Packagers
Dosage forms
Form Route Strength
Injection, solution Intravenous 0.05 mg/ml
Injection, solution, concentrate Intravenous 0.8 mg/ml
Prices
Unit description Cost Unit
Zometa 4 mg/5ml Concentrate 5ml Vial 1095.69 USD vial
Reclast 5 mg/100ml Solution 13.39 USD ml
Reclast 5 mg/100 ml solution 12.88 USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
United States 4939130 1993-03-02 2013-03-02
Canada 1338937 1997-02-25 2014-02-25
Canada 1338895 1997-02-04 2014-02-04
Properties
State solid
Experimental Properties
Property Value Source
water solubility Sparingly soluble Not Available
logP -4.2 Not Available
Predicted Properties
Property Value Source
water solubility 3.27e+00 g/l ALOGPS
logP -0.93 ALOGPS
logP -3.9 ChemAxon
logS -1.9 ALOGPS
pKa (strongest acidic) 0.66 ChemAxon
pKa (strongest basic) 6.67 ChemAxon
physiological charge -2 ChemAxon
hydrogen acceptor count 8 ChemAxon
hydrogen donor count 5 ChemAxon
polar surface area 153.11 ChemAxon
rotatable bond count 4 ChemAxon
refractivity 52.16 ChemAxon
polarizability 20.1 ChemAxon
References
Synthesis Reference Not Available
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
Resource Link
KEGG Drug D01968 Link_out
PubChem Compound 68740 Link_out
PubChem Substance 46507310 Link_out
ChemSpider 61986 Link_out
BindingDB 12578 Link_out
Therapeutic Targets Database DAP001539 Link_out
PharmGKB PA10235 Link_out
HET ZOL Link_out
Drug Product Database 2242725 Link_out
RxList http://www.rxlist.com/cgi/generic/zometa.htm Link_out
Wikipedia http://en.wikipedia.org/wiki/Zoledronate Link_out
ATC Codes
  • M05BA08
AHFS Codes
  • 92:00.00
PDB Entries Not Available
FDA label Not Available
MSDS show (57.9 KB)
Interactions
Drug Interactions Searched, but no interactions found.
Food Interactions Not Available
Targets

1. Farnesyl pyrophosphate synthetase

Pharmacological action: yes
Actions: inhibitor

Catalyzes the sequential condensation of isopentenyl pyrophosphate with the allylic pyrophosphates, dimethylallyl pyrophosphate, and then with the resultant geranylpyrophosphate to the ultimate product farnesyl pyrophosphate

Organism class: human
UniProt ID: P14324 Link_out
Gene: FDPS Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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 synthetase

Pharmacological action: yes
Actions: inhibitor

Catalyzes the trans-addition of the three molecules of IPP onto DMAPP to form geranylgeranyl pyrophosphate, an important precursor of carotenoids and geranylated proteins

Organism class: human
UniProt ID: O95749 Link_out
Gene: GGPS1 Link_out
Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

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. Hydroxyapatite

Pharmacological action: yes
Actions: antagonist

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

Actions: substrate

May participate directly in the active transport of drugs into subcellular organelles or influence drug distribution indirectly. Confers resistance to anticancer drugs. Transports LTC4. May protect milk against xenobiotics

UniProt ID: P33527 Link_out
Gene: ABCC1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19