Clodronic acid
Identification
- Name
- Clodronic acid
- Accession Number
- DB00720 (APRD00639)
- Type
- Small Molecule
- Groups
- Approved, Investigational, Vet approved
- Description
Clodronic acid is a diphosphonate which affects calcium metabolism. It inhibits bone resorption and soft tissue calcification.
- Structure
Structure for Clodronic acid (DB00720)
- Synonyms
- (Dichloro-phosphono-methyl)-phosphonic acid
- (dichloromethylene)bisphosphonic acid
- (dichloromethylene)diphosphonic acid
- Acide clodronique
- Acido clodronico
- Acidum clodronicum
- Clodronate
- Clodronic acid
- Clodronsaeure
- Clodronsäure
- dichloromethylene-1,1-bisphosphonic acid
- dichloromethylene-1,1-diphosphonic acid
- Dichloromethylidene diphosphonate
- External IDs
- BM 06.011
- Product Ingredients
Ingredient UNII CAS InChI Key Clodronate disodium N030400H8J 88416-50-6 XWHPUCFOTRBMGS-UHFFFAOYSA-L Clodronate disodium tetrahydrate Not Available Not Available Not applicable - Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Unlock Additional DataBonefos Solution 60 mg Intravenous Bayer 1992-12-31 Not applicable Canada 
Bonefos Capsule 400 mg Oral Bayer 1992-12-31 Not applicable Canada Clasteon Capsule 400 mg Oral Sunovion 2004-05-13 Not applicable Canada Ostac Cap 400mg Capsule 400 mg Oral Hoffmann La Roche 1994-12-31 2006-10-11 Canada Additional Data Available- Application NumberApplication Number
A unique ID assigned by the FDA when a product is submitted for approval by the labeller.
Learn more - Product CodeProduct Code
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.
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- International/Other Brands
- Lodronat (Boehringer Ingelheim) / Loron (Roche) / Lytos (Roche) / Ostac (Roche) / Sindronat (Sindan)
- Categories
- UNII
- 0813BZ6866
- CAS number
- 10596-23-3
- Weight
- Average: 244.892
Monoisotopic: 243.886016298 - Chemical Formula
- CH4Cl2O6P2
- InChI Key
- 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
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.
- Associated Conditions
- 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.
Target Actions Organism AADP/ATP translocase 1 inhibitorHumans AADP/ATP translocase 2 inhibitorHumans AADP/ATP translocase 3 inhibitorHumans AHydroxylapatite antagonistHumans - 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
- Pharmacogenomic Effects/ADRs
- Not Available
Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.
Learn moreStructured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.
Learn moreStructured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.
Learn moreInteractions
- Drug Interactions
Drug Interaction Unlock Additional DataAceclofenac The risk or severity of gastrointestinal bleeding can be increased when Aceclofenac is combined with Clodronic acid. Acemetacin The risk or severity of gastrointestinal bleeding can be increased when Acemetacin is combined with Clodronic acid. Acetylsalicylic acid The risk or severity of gastrointestinal bleeding can be increased when Acetylsalicylic acid is combined with Clodronic acid. Acyclovir The risk or severity of nephrotoxicity and hypocalcemia can be increased when Acyclovir is combined with Clodronic acid. Adefovir The risk or severity of nephrotoxicity and hypocalcemia can be increased when Adefovir is combined with Clodronic acid. Adefovir dipivoxil The risk or severity of nephrotoxicity and hypocalcemia can be increased when Adefovir Dipivoxil is combined with Clodronic acid. Alclofenac The risk or severity of gastrointestinal bleeding can be increased when Alclofenac is combined with Clodronic acid. Alendronic acid The risk or severity of hypocalcemia can be increased when Alendronic acid is combined with Clodronic acid. Almasilate The serum concentration of Clodronic acid can be decreased when it is combined with Almasilate. Alminoprofen The risk or severity of gastrointestinal bleeding can be increased when Alminoprofen is combined with Clodronic acid. Additional Data Available- Extended DescriptionExtended Description
Extended description of the mechanism of action and particular properties of each drug interaction.
Learn more - Severity
- Evidence Level
- ActionEvidence Level
An effect category for each drug interaction. Know how this interaction affects the subject drug.
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- Food Interactions
- Food decreases absorption. Take on an empty stomach.
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 References
- Not Available
- External Links
- Human Metabolome Database
- HMDB0014858
- PubChem Compound
- 25419
- PubChem Substance
- 46508646
- ChemSpider
- 23731
- BindingDB
- 50216172
- ChEBI
- 110423
- ChEMBL
- CHEMBL12318
- Therapeutic Targets Database
- DAP000564
- PharmGKB
- PA10239
- Wikipedia
- Clodronate
- ATC Codes
- M05BA02 — Clodronic acid
- AHFS Codes
- 92:24.00 — Bone Resorption Inhibitors
- MSDS
- Download (120 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 0 Completed Treatment Osteoarthritis, Hip 1 2 Unknown Status Treatment Aseptic Loosening of the Hip Prosthesis 1 3 Active Not Recruiting Treatment Cancer, Breast 1 3 Completed Treatment Cancer, Breast 1 3 Completed Treatment Pain NOS / Prostate Cancer / Quality of Life 1 3 Completed Treatment Postmenopausal Osteoporosis (PMO) 1 3 Completed Treatment Radiation Induced Brachial Plexopathy 1 Not Available Completed Not Available Bone Neoplasms 1 Not Available Completed Not Available Multiple Myeloma (MM) / Neoplasms, Breast / Osteolysis / Prostatic Neoplasms 1 Not Available Completed Treatment Osteoporosis 1 Not Available Withdrawn Not Available Cancer, Breast 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage forms
Form Route Strength Solution Intravenous 60 mg Capsule Oral 400 mg - Prices
Unit description Cost Unit Bonefos 60 mg/ml 13.69USD ml Bonefos 400 mg Capsule 2.04USD capsule Clasteon 400 mg Capsule 1.36USD capsule DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 250 °C PhysProp water solubility 395 mg/L Not Available logP -2.4 Not Available - Predicted Properties
Property Value Source Water Solubility 7.47 mg/mL ALOGPS logP 0.16 ALOGPS logP -0.067 ChemAxon logS -1.5 ALOGPS pKa (Strongest Acidic) 0.62 ChemAxon Physiological Charge -3 ChemAxon Hydrogen Acceptor Count 6 ChemAxon Hydrogen Donor Count 4 ChemAxon Polar Surface Area 115.06 Å2 ChemAxon Rotatable Bond Count 2 ChemAxon Refractivity 38.21 m3·mol-1 ChemAxon Polarizability 15.3 Å3 ChemAxon Number of Rings 0 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter No ChemAxon Veber's Rule No ChemAxon MDDR-like Rule No ChemAxon - Predicted ADMET features
Property Value Probability Human Intestinal Absorption - 0.8406 Blood Brain Barrier + 0.9481 Caco-2 permeable - 0.8956 P-glycoprotein substrate Non-substrate 0.8597 P-glycoprotein inhibitor I Non-inhibitor 0.9701 P-glycoprotein inhibitor II Non-inhibitor 0.9903 Renal organic cation transporter Non-inhibitor 0.958 CYP450 2C9 substrate Non-substrate 0.7693 CYP450 2D6 substrate Non-substrate 0.8234 CYP450 3A4 substrate Non-substrate 0.697 CYP450 1A2 substrate Non-inhibitor 0.8539 CYP450 2C9 inhibitor Non-inhibitor 0.8878 CYP450 2D6 inhibitor Non-inhibitor 0.9091 CYP450 2C19 inhibitor Non-inhibitor 0.8449 CYP450 3A4 inhibitor Non-inhibitor 0.9061 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9743 Ames test Non AMES toxic 0.7328 Carcinogenicity Carcinogens 0.6575 Biodegradation Not ready biodegradable 0.927 Rat acute toxicity 2.6142 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9321 hERG inhibition (predictor II) Non-inhibitor 0.9427
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS Not Available Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
Taxonomy
- Description
- This 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.
- Kingdom
- Organic compounds
- Super Class
- Organic acids and derivatives
- Class
- Organic phosphonic acids and derivatives
- Sub Class
- Bisphosphonates
- Direct Parent
- Bisphosphonates
- Alternative Parents
- Organic phosphonic acids / Organopnictogen compounds / Organophosphorus compounds / Organochlorides / Organic oxides / Hydrocarbon derivatives / Alkyl chlorides
- Substituents
- Bisphosphonate / Organophosphonic acid / Organic oxygen compound / Organopnictogen compound / Organic oxide / Hydrocarbon derivative / Organophosphorus compound / Organochloride / Organohalogen compound / Alkyl halide
- Molecular Framework
- Aliphatic acyclic compounds
- External Descriptors
- one-carbon compound, organochlorine compound, 1,1-bis(phosphonic acid) (CHEBI:110423)
Targets
- Kind
- Protein
- Organism
- Humans
- 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
- Uniprot Name
- ADP/ATP translocase 1
- Molecular Weight
- 33064.265 Da
References
- 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]
- 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
- Humans
- 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 seg...
- Gene Name
- SLC25A5
- Uniprot ID
- P05141
- Uniprot Name
- ADP/ATP translocase 2
- Molecular Weight
- 32851.965 Da
References
- 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
- Humans
- 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) respons...
- Gene Name
- SLC25A6
- Uniprot ID
- P12236
- Uniprot Name
- ADP/ATP translocase 3
- Molecular Weight
- 32866.025 Da
References
- 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]
References
- 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]
- 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
- Humans
- 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...
- Gene Name
- PTGS2
- Uniprot ID
- P35354
- Uniprot Name
- Prostaglandin G/H synthase 2
- Molecular Weight
- 68995.625 Da
References
- 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]
Drug created on June 13, 2005 07:24 / Updated on May 24, 2019 23:15