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Identification
Name Clodronate
Accession Number DB00720 (APRD00639)
Type small molecule
Groups approved
Description

A diphosphonate which affects calcium metabolism. It inhibits bone resorption and soft tissue calcification. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Synonyms Not Available
Salts Not Available
Brand names
Name Company
Acide Clodronique [INN-French]
Acido Clodronico [INN-Spanish]
Acidum Clodronicum [INN-Latin]
Bonefos Bayer
Clasteon Sepracor
Dichloromethanediphosphonic acid
Dichloromethylidene diphosphonate
Loron
Ostac
Brand mixtures Not Available
Categories
  • Antineoplastic Agents
  • Antihypocalcemic Agents
  • Bisphosphonates
  • Osteoporosis Prophylactic
  • Bone Density Conservation Agents
CAS number 10596-23-3
Weight Average: 244.892
Monoisotopic: 243.886016298
Chemical Formula CH4Cl2O6P2
InChI Key InChIKey=ACSIXWWBWUQEHA-UHFFFAOYSA-N
InChI
InChI=1S/CH4Cl2O6P2/c2-1(3,10(4,5)6)11(7,8)9/h(H2,4,5,6)(H2,7,8,9)
Plain Text
IUPAC Name
[dichloro(phosphono)methyl]phosphonic acid
SMILES
OP(O)(=O)C(Cl)(Cl)P(O)(O)=O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Bisphosphonates
Substructures
  • Hydroxy Compounds
  • Phosphonic Acids and Derivatives
  • Halogen Derivatives
  • Phosphinic Acids and Derivatives
  • Bisphosphonates
Pharmacology
Indication For the management of hypercalcemia of malignancy and as an adjunct in the management of osteolysis resulting from bone metastases of malignant tumors.
Pharmacodynamics Clodronate is a first generation (non-nitrogenous) bisphosphonate in the same family as etidronate and tiludronate. Clodronate affects calcium metabolism and inhibits bone resorption and soft tissue calcification. Of the clodronate that is resorbed (from oral preparation) or infused (for intravenous drugs), about 50% is excreted unchanged by the kidney. The remainder has a very high affinity for bone tissue, and is rapidly absorbed onto the bone surface. Clodronate has been shown to prevent or delay skeletal-related events and decrease bone pain as well as normalize calcium levels in the presence of hypercalcemia.
Mechanism of action The bisphosphonate group binds strongly to the bone mineral, hydroxyapatite. This explains the specific pharmacological action of these compounds on mineralized tissues, especially bone. The exact mechanism of action of clodronate is not known, however it is known that it does not inhibit protein isoprenylation but can be metabolized intracellularly to a β-γ-methylene (AppCp-type) analog of ATP (AppCCl2p), which is cytotoxic to macrophages in vitro. Inhibition of the ADP/ATP translocase by the metabolite AppCCl2p is a likely route by which clodronate causes osteoclast apoptosis and inhibits bone resorption. Recently, the slime mold Dictyostelium discoideum was shown to take up bisphosphonates by pinocytosis. In these cells, clodronate, but not other pharmacologically active bisphosphonates, was incorporated into adenine nucleotides, which could potentially explain why this bisphosphonate sometimes seems to act differently than the other bisphosphonates. Clodronate, like all biphosphonates, also binds protein-tyrosine-phosphatase.
Absorption After oral administration, absorption is estimated at 1–3% of the ingested dose because of the low uptake from the gastrointestinal tract.
Volume of distribution Not Available
Protein binding 2%-36%
Metabolism Clodronate is not metabolized in humans.
Route of elimination Not Available
Half life Approximately 13 hours.
Clearance Not Available
Toxicity Decreases in serum calcium following substantial overdosage may be expected in some patients. Signs and symptoms of hypocalcemia also may occur in some of these patients.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers Not Available
Packagers Not Available
Dosage forms
Form Route Strength
Capsule Oral 400 mg
Solution Intravenous 30 mg/ml
Solution Intravenous 60 mg/ml
Prices
Unit description Cost Unit
Bonefos 60 mg/ml 13.69 USD ml
Bonefos 400 mg Capsule 2.04 USD capsule
Clasteon 400 mg Capsule 1.36 USD capsule
Patents Not Available
Properties
State solid
Melting point 250 oC
Experimental Properties
Property Value Source
water solubility 395 mg/L PhysProp
logP -2.4 PhysProp
Predicted Properties
Property Value Source
water solubility 7.47e+00 g/l ALOGPS
logP 0.16 ALOGPS
logP -0.067 ChemAxon Molconvert
logS -1.5 ALOGPS
pKa 1.38 ChemAxon Molconvert
hydrogen acceptor count 6 ChemAxon Molconvert
hydrogen donor count 4 ChemAxon Molconvert
polar surface area 115.06 ChemAxon Molconvert
rotatable bond count 2 ChemAxon Molconvert
refractivity 38.21 ChemAxon Molconvert
polarizability 15.3 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
PubChem Compound 25419 Link_out
PubChem Substance 46508646 Link_out
ChemSpider 23731 Link_out
BindingDB 50216172 Link_out
ChEBI 110423 Link_out
ChEMBL 110423 Link_out
Therapeutic Targets Database DAP000564 Link_out
PharmGKB PA10239 Link_out
Drug Product Database 1984837 Link_out
Wikipedia http://en.wikipedia.org/wiki/Clodronate Link_out
ATC Codes
  • M05BA02
AHFS Codes
  • 92:00.00
PDB Entries Not Available
FDA label Not Available
MSDS show (120 KB)
Interactions
Drug Interactions
Drug Interaction
Aluminium Formation of non-absorbable complexes
Calcium Formation of non-absorbable complexes
Calcium Acetate Calcium Salts may decrease the serum concentration of Bisphosphonate Derivatives such as clodronate. Avoid administration of oral calcium supplements within 2 hours before or after tiludronate/clodronate/etidronate.
Calcium Chloride Calcium salts may decrease the serum concentration of bisphosphonate derivatives. Avoid administration of oral calcium supplements within 2 hours before or after tiludronate/clodronate/etidronate.
Dihydroxyaluminium Formation of non-absorbable complexes
Estramustine Clodronate may increase the levels of estramustine.
Iron Formation of non-absorbable complexes
Iron Dextran Formation of non-absorbable complexes
Magnesium Formation of non-absorbable complexes
Magnesium oxide Formation of non-absorbable complexes
Sucralfate Formation of non-absorbable complexes
Food Interactions
  • Food decreases absorption. Take on an empty stomach.
Targets

1. ADP/ATP translocase 1

Pharmacological action: yes
Actions: inhibitor

Catalyzes the exchange of ADP and ATP across the mitochondrial inner membrane

Organism class: human
UniProt ID: P12235 Link_out
Gene: SLC25A4 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Lehenkari PP, Kellinsalmi M, Napankangas JP, Ylitalo KV, Monkkonen J, Rogers MJ, Azhayev A, Vaananen HK, Hassinen IE: Further insight into mechanism of action of clodronate: inhibition of mitochondrial ADP/ATP translocase by a nonhydrolyzable, adenine-containing metabolite. Mol Pharmacol. 2002 May;61(5):1255-62. Pubmed
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. ADP/ATP translocase 2

Pharmacological action: yes
Actions: inhibitor

Catalyzes the exchange of ADP and ATP across the mitochondrial inner membrane

Organism class: human
UniProt ID: P05141 Link_out
Gene: SLC25A5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Lehenkari PP, Kellinsalmi M, Napankangas JP, Ylitalo KV, Monkkonen J, Rogers MJ, Azhayev A, Vaananen HK, Hassinen IE: Further insight into mechanism of action of clodronate: inhibition of mitochondrial ADP/ATP translocase by a nonhydrolyzable, adenine-containing metabolite. Mol Pharmacol. 2002 May;61(5):1255-62. Pubmed

3. ADP/ATP translocase 3

Pharmacological action: yes
Actions: inhibitor

Catalyzes the exchange of ADP and ATP across the mitochondrial inner membrane. May participate in the formation of the permeability transition pore complex (PTPC) responsible for the release of mitochondrial products that triggers apoptosis

Organism class: human
UniProt ID: P12236 Link_out
Gene: SLC25A6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Lehenkari PP, Kellinsalmi M, Napankangas JP, Ylitalo KV, Monkkonen J, Rogers MJ, Azhayev A, Vaananen HK, Hassinen IE: Further insight into mechanism of action of clodronate: inhibition of mitochondrial ADP/ATP translocase by a nonhydrolyzable, adenine-containing metabolite. Mol Pharmacol. 2002 May;61(5):1255-62. Pubmed

4. Hydroxyapatite

Pharmacological action: yes
Actions: antagonist

References:
  1. Ganguli A, Steward C, Butler SL, Philips GJ, Meikle ST, Lloyd AW, Grant MH: Bacterial adhesion to bisphosphonate coated hydroxyapatite. J Mater Sci Mater Med. 2005 Apr;16(4):283-7. 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
Comments
Drug created on June 13, 2005 07:24 / Updated on February 14, 2012 11:43