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Identification
NameClodronate
Accession NumberDB00720  (APRD00639)
TypeSmall Molecule
GroupsApproved, Investigational, Vet Approved
Description

A diphosphonate which affects calcium metabolism. It inhibits bone resorption and soft tissue calcification. [PubChem]

Structure
Thumb
Synonyms
(Dichloro-phosphono-methyl)-phosphonic acid
(Dichloromethylene)bisphosphonic acid
(Dichloromethylene)diphosphonic acid
Acide Clodronique
Acido Clodronico
Acidum Clodronicum
Clodronate
Clodronsaeure
Clodronsäure
Dichloromethanediphosphonic acid
Dichloromethylene-1,1-bisphosphonic acid
Dichloromethylene-1,1-diphosphonic acid
Dichloromethylidene diphosphonate
External Identifiers
  • BM 06.011
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Bonefossolution60 mgintravenousBayer Inc1992-12-31Not applicableCanada
Bonefoscapsule400 mgoralBayer Inc1992-12-31Not applicableCanada
Clasteoncapsule400 mgoralSunovion Pharmaceuticals Canada Inc2004-05-13Not applicableCanada
Ostac Cap 400mgcapsule400 mgoralHoffmann La Roche Limited1994-12-312006-10-11Canada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
LodronatBoehringer Ingelheim
LoronRoche
LytosRoche
OstacRoche
SindronatSindan
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Clodronate disodium
ThumbNot applicableDBSALT000972
Clodronate disodium tetrahydrate
ThumbNot applicableDBSALT001199
Categories
UNII0813BZ6866
CAS number10596-23-3
WeightAverage: 244.892
Monoisotopic: 243.886016298
Chemical FormulaCH4Cl2O6P2
InChI KeyInChIKey=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)
IUPAC Name
[dichloro(phosphono)methyl]phosphonic acid
SMILES
OP(O)(=O)C(Cl)(Cl)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
  • Organophosphonic acid
  • Halomethane
  • Hydrocarbon derivative
  • Organochloride
  • Organohalogen compound
  • Alkyl halide
  • Alkyl chloride
  • Aliphatic acyclic compound
Molecular FrameworkAliphatic acyclic compounds
External Descriptors
Pharmacology
IndicationFor the management of hypercalcemia of malignancy and as an adjunct in the management of osteolysis resulting from bone metastases of malignant tumors.
PharmacodynamicsClodronate 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 actionThe 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.
Related Articles
AbsorptionAfter oral administration, absorption is estimated at 1–3% of the ingested dose because of the low uptake from the gastrointestinal tract.
Volume of distributionNot Available
Protein binding2%-36%
Metabolism

Clodronate is not metabolized in humans.

Route of eliminationNot Available
Half lifeApproximately 13 hours.
ClearanceNot Available
ToxicityDecreases 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
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.8406
Blood Brain Barrier+0.9481
Caco-2 permeable-0.8956
P-glycoprotein substrateNon-substrate0.8597
P-glycoprotein inhibitor INon-inhibitor0.9701
P-glycoprotein inhibitor IINon-inhibitor0.9903
Renal organic cation transporterNon-inhibitor0.958
CYP450 2C9 substrateNon-substrate0.7693
CYP450 2D6 substrateNon-substrate0.8234
CYP450 3A4 substrateNon-substrate0.697
CYP450 1A2 substrateNon-inhibitor0.8539
CYP450 2C9 inhibitorNon-inhibitor0.8878
CYP450 2D6 inhibitorNon-inhibitor0.9091
CYP450 2C19 inhibitorNon-inhibitor0.8449
CYP450 3A4 inhibitorNon-inhibitor0.9061
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9743
Ames testNon AMES toxic0.7328
CarcinogenicityCarcinogens 0.6575
BiodegradationNot ready biodegradable0.927
Rat acute toxicity2.6142 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9321
hERG inhibition (predictor II)Non-inhibitor0.9427
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Capsuleoral400 mg
Solutionintravenous60 mg
Prices
Unit descriptionCostUnit
Bonefos 60 mg/ml13.69USD ml
Bonefos 400 mg Capsule2.04USD capsule
Clasteon 400 mg Capsule1.36USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point250 °CPhysProp
water solubility395 mg/LNot Available
logP-2.4Not Available
Predicted Properties
PropertyValueSource
Water Solubility7.47 mg/mLALOGPS
logP0.16ALOGPS
logP-0.067ChemAxon
logS-1.5ALOGPS
pKa (Strongest Acidic)0.62ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area115.06 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity38.21 m3·mol-1ChemAxon
Polarizability15.3 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Fritz Demmer, Berthold Stemmle, “Clodronate-containing medicaments and a process for the preparation thereof.” U.S. Patent US4859472, issued September, 1980.

US4859472
General ReferencesNot Available
External Links
ATC CodesNot Available
AHFS Codes
  • 92:00.00
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (120 KB)
Interactions
Drug Interactions
Drug
Aluminum hydroxideThe serum concentration of Clodronate can be decreased when it is combined with Aluminum hydroxide.
AmikacinAmikacin may increase the activities of Clodronate.
ArbekacinArbekacin may increase the activities of Clodronate.
BevacizumabThe risk or severity of adverse effects can be increased when Bevacizumab is combined with Clodronate.
Calcium carbonateThe serum concentration of Clodronate can be decreased when it is combined with Calcium carbonate.
DeferasiroxThe risk or severity of adverse effects can be increased when Clodronate is combined with Deferasirox.
EsomeprazoleThe therapeutic efficacy of Clodronate can be decreased when used in combination with Esomeprazole.
EstramustineThe serum concentration of Estramustine can be increased when it is combined with Clodronate.
FramycetinFramycetin may increase the activities of Clodronate.
GentamicinGentamicin may increase the activities of Clodronate.
InfliximabThe risk or severity of adverse effects can be increased when Infliximab is combined with Clodronate.
Iron DextranThe serum concentration of Clodronate can be decreased when it is combined with Iron Dextran.
KanamycinKanamycin may increase the activities of Clodronate.
LansoprazoleThe therapeutic efficacy of Clodronate can be decreased when used in combination with Lansoprazole.
Magnesium oxideThe serum concentration of Clodronate can be decreased when it is combined with Magnesium oxide.
Magnesium SulfateThe serum concentration of Clodronate can be decreased when it is combined with Magnesium Sulfate.
NeomycinNeomycin may increase the activities of Clodronate.
NetilmicinNetilmicin may increase the activities of Clodronate.
OmeprazoleThe therapeutic efficacy of Clodronate can be decreased when used in combination with Omeprazole.
PantoprazoleThe therapeutic efficacy of Clodronate can be decreased when used in combination with Pantoprazole.
RibostamycinRibostamycin may increase the activities of Clodronate.
SpectinomycinSpectinomycin may increase the activities of Clodronate.
StreptomycinStreptomycin may increase the activities of Clodronate.
TobramycinTobramycin may increase the activities of Clodronate.
Food Interactions
  • Food decreases absorption. Take on an empty stomach.

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Adenine transmembrane transporter activity
Specific Function:
Catalyzes the exchange of cytoplasmic ADP with mitochondrial ATP across the mitochondrial inner membrane.
Gene Name:
SLC25A4
Uniprot ID:
P12235
Molecular Weight:
33064.265 Da
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:11961144 ]
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Ubiquitin protein ligase binding
Specific Function:
Catalyzes the exchange of cytoplasmic ADP with mitochondrial ATP across the mitochondrial inner membrane. As part of the mitotic spindle-associated MMXD complex it may play a role in chromosome segregation.
Gene Name:
SLC25A5
Uniprot ID:
P05141
Molecular Weight:
32851.965 Da
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:11961144 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Atp:adp antiporter activity
Specific Function:
Catalyzes the exchange of cytoplasmic ADP with mitochondrial 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.
Gene Name:
SLC25A6
Uniprot ID:
P12236
Molecular Weight:
32866.025 Da
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:11961144 ]
Kind
Small molecule
Organism
Human
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:15803271 ]
  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:16046206 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Prostaglandin-endoperoxide synthase activity
Specific Function:
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and brain, and in pathological conditions, such as in cancer. PTGS2 is responsible for production of inflammatory prostaglandins. Up-regulation of PTGS2 is also associated with increased cell adhesion, p...
Gene Name:
PTGS2
Uniprot ID:
P35354
Molecular Weight:
68995.625 Da
References
  1. Liu L, Igarashi K, Kanzaki H, Chiba M, Shinoda H, Mitani H: Clodronate inhibits PGE(2) production in compressed periodontal ligament cells. J Dent Res. 2006 Aug;85(8):757-60. [PubMed:16861295 ]
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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:11