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
Thumb
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
IngredientUNIICASInChI Key
Clodronate disodiumN030400H8J88416-50-6XWHPUCFOTRBMGS-UHFFFAOYSA-L
Clodronate disodium tetrahydrateNot AvailableNot AvailableNot applicable
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
BonefosSolution60 mgIntravenousBayer1992-12-31Not applicableCanada
BonefosCapsule400 mgOralBayer1992-12-31Not applicableCanada
ClasteonCapsule400 mgOralSunovion2004-05-13Not applicableCanada
Ostac Cap 400mgCapsule400 mgOralHoffmann La Roche1994-12-312006-10-11Canada
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.

TargetActionsOrganism
AADP/ATP translocase 1
inhibitor
Human
AADP/ATP translocase 2
inhibitor
Human
AADP/ATP translocase 3
inhibitor
Human
AHydroxylapatite
antagonist
Human
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

Interactions

Drug Interactions
DrugInteraction
AceclofenacThe risk or severity of gastrointestinal bleeding can be increased when Aceclofenac is combined with Clodronic Acid.
AcemetacinThe risk or severity of gastrointestinal bleeding can be increased when Acemetacin is combined with Clodronic Acid.
Acetylsalicylic acidThe risk or severity of gastrointestinal bleeding can be increased when Acetylsalicylic acid is combined with Clodronic Acid.
AcyclovirThe risk or severity of nephrotoxicity and hypocalcemia can be increased when Acyclovir is combined with Clodronic Acid.
AdefovirThe risk or severity of nephrotoxicity and hypocalcemia can be increased when Adefovir is combined with Clodronic Acid.
Adefovir DipivoxilThe risk or severity of nephrotoxicity and hypocalcemia can be increased when Adefovir Dipivoxil is combined with Clodronic Acid.
AlclofenacThe risk or severity of gastrointestinal bleeding can be increased when Alclofenac is combined with Clodronic Acid.
Alendronic acidThe risk or severity of hypocalcemia can be increased when Alendronic acid is combined with Clodronic Acid.
AlmasilateThe serum concentration of Clodronic Acid can be decreased when it is combined with Almasilate.
AlminoprofenThe risk or severity of gastrointestinal bleeding can be increased when Alminoprofen is combined with Clodronic Acid.
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
PhaseStatusPurposeConditionsCount
2Unknown StatusTreatmentAseptic Loosening of the Hip Prosthesis1
3Active Not RecruitingTreatmentCancer, Breast1
3CompletedTreatmentCancer, Breast1
3CompletedTreatmentPain NOS / Prostate Cancer / Quality of Life1
3CompletedTreatmentPostmenopausal Osteoporosis (PMO)1
3CompletedTreatmentRadiation Induced Brachial Plexopathy1
Not AvailableCompletedNot AvailableBone Neoplasms1
Not AvailableCompletedNot AvailableMultiple Myeloma (MM) / Neoplasms, Breast / Osteolysis / Prostatic Neoplasms1
Not AvailableCompletedTreatmentOsteoporosis1
Not AvailableWithdrawnNot AvailableCancer, Breast1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
SolutionIntravenous60 mg
CapsuleOral400 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.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)250 °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-3ChemAxon
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 FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot 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
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
Uniprot Name
ADP/ATP translocase 1
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 seg...
Gene Name
SLC25A5
Uniprot ID
P05141
Uniprot Name
ADP/ATP translocase 2
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) respons...
Gene Name
SLC25A6
Uniprot ID
P12236
Uniprot Name
ADP/ATP translocase 3
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...
Gene Name
PTGS2
Uniprot ID
P35354
Uniprot Name
Prostaglandin G/H synthase 2
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]

Drug created on June 13, 2005 07:24 / Updated on December 14, 2018 17:07