Identification

Name
Clodronic acid
Accession Number
DB00720
Description

Clodronic acid is a first generation bisphosphonate similar to etidronic acid and tiludronic acid.1 These drugs were developed to mimic the action of pyrophosphate, a regulator of calcification and decalcification.2 clodronate’s use has decreased over the years in favor of the third generation, nitrogen containing bisphosphonate zoledronic acid, ibandronic acid, minodronic acid, and risedronic acid.1

Clodronic acid is not FDA approved, but is approved in Canada.8

Type
Small Molecule
Groups
Approved, Investigational, Vet approved
Structure
Thumb
Weight
Average: 244.892
Monoisotopic: 243.886016298
Chemical Formula
CH4Cl2O6P2
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

Pharmacology

Indication

Clodronic acid is indicated as an adjunct in the management of osteolysis from bone metastases of malignant tumors and for management of hypercalcemia of malignancy.8

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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Pharmacodynamics

Clodronic acid is a first generation bisphosphonate that inhibits osteoclast mediated bone resorption.8 It has a wide therapeutic index as a large overdose is required for significant toxicity and a long duration of action due to the slow release from bone.8 Patients should be counselled regarding the risk of hypocalcemia, hypovolemia, renal insufficiency, transient hyperphosphatemia, and transient hyperparathyroidism.8

Mechanism of action

Bisphosphonates are taken into the bone where they bind to hydroxyapatite. Bone resorption by osteoclasts causes local acidification, releasing the bisphosphonate, which is taken into the osteoclast by fluid-phase endocytosis.5 Endocytic vesicles become acidified, releasing bisphosphonates into the cytosol of osteoclasts where they act.5

Osteoclasts mediate resorption of bone.6 When osteoclasts bind to bone they form podosomes, ring structures of F-actin.6 Disruption of the podosomes causes osteoclasts to detach from bones, preventing bone resorption.6

First generation bisphosphonates closely mimic the structure of pyrophosphate, which can be incorporated into ATP anologues that cannot be hydrolyzed, disrupting all ATP mediated actions of osteoclasts.7

TargetActionsOrganism
AHydroxylapatite
antagonist
Humans
AADP/ATP translocase 1
inhibitor
Humans
AADP/ATP translocase 2
inhibitor
Humans
AADP/ATP translocase 3
inhibitor
Humans
Absorption

Oral clodronic acid has a bioavailability of 1-2%.4 A 200mg intravenous dose reaches a Cmax of 16.1mg/L with an AUC of 44.2mg*h/L.4 A 200mg intramuscular dose reaches a Cmax of 12.8mg/L with an AUC of 47.5mg*h/L.4 Further pharmacokinetic data for clodronic acid are not readily available.8

Volume of distribution
Not Available
Protein binding

Clodronic acid is 36% protein bound in plasma.3

Metabolism

Clodronate is not metabolized in humans.8

Route of elimination

Clodronate is eliminated unchanged in the urine.8

Half-life

The mean plasma half life of clodronate is 5.6h.8

Clearance

The renal clearance of clodronate is approximately 90mL/min.8

Adverse Effects
Learn about our commercial Adverse Effects data.
Learn More
Toxicity

Patients experiencing an overdose may present with hypocalcemia, while severe overdoses can present with kidney failure, liver damage, and unconsciousness.8 Overdose can be managed through symptomatic and supportive care, including monitoring and administration of electrolytes including calcium.8 Gastric lavage may remove unabsorbed drug in the gastrointestinal tract.8

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
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.
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 adverse effects 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.
AluminiumThe serum concentration of Clodronic acid can be decreased when it is combined with Aluminium.
Aluminium phosphateThe serum concentration of Clodronic acid can be decreased when it is combined with Aluminium phosphate.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

    Learn more
  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Take on an empty stomach. Co-administration with food may decrease absorption.

Products

Product Ingredients
IngredientUNIICASInChI Key
Clodronate disodiumN030400H8J88416-50-6XWHPUCFOTRBMGS-UHFFFAOYSA-L
Clodronate disodium tetrahydrateNot AvailableNot AvailableNot applicable
International/Other Brands
Lodronat (Boehringer Ingelheim) / Loron (Roche) / Lytos (Roche) / Ostac (Roche) / Sindronat (Sindan)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
BonefosSolutionIntravenousBayer1992-12-312018-12-27Canada flag
BonefosCapsuleOralBayer1992-12-312018-03-27Canada flag
ClasteonCapsuleOralSunovion2004-05-13Not applicableCanada flag
Ostac Cap 400mgCapsuleOralHoffmann La Roche1994-12-312006-10-11Canada flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

    Learn more
  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

    Learn more

Categories

ATC Codes
M05BA02 — Clodronic acid
Drug Categories
Chemical TaxonomyProvided by Classyfire
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
Aliphatic acyclic compound / Alkyl chloride / Alkyl halide / Bisphosphonate / Hydrocarbon derivative / Organic oxide / Organic oxygen compound / Organochloride / Organohalogen compound / Organophosphonic acid
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
one-carbon compound, organochlorine compound, 1,1-bis(phosphonic acid) (CHEBI:110423)

Chemical Identifiers

UNII
0813BZ6866
CAS number
10596-23-3
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

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
  1. Cremers S, Drake MT, Ebetino FH, Bilezikian JP, Russell RGG: Pharmacology of bisphosphonates. Br J Clin Pharmacol. 2019 Jun;85(6):1052-1062. doi: 10.1111/bcp.13867. Epub 2019 Feb 28. [PubMed:30650219]
  2. Sansom LN, Necciari J, Thiercelin JF: Human pharmacokinetics of tiludronate. Bone. 1995 Nov;17(5 Suppl):479S-483S. [PubMed:8573422]
  3. Pentikainen PJ, Elomaa I, Nurmi AK, Karkkainen S: Pharmacokinetics of clodronate in patients with metastatic breast cancer. Int J Clin Pharmacol Ther Toxicol. 1989 May;27(5):222-8. [PubMed:2525532]
  4. Frediani B, Cavalieri L, Cremonesi G: Clodronic acid formulations available in Europe and their use in osteoporosis: a review. Clin Drug Investig. 2009;29(6):359-79. doi: 10.2165/00044011-200929060-00001. [PubMed:19432497]
  5. Russell RG, Watts NB, Ebetino FH, Rogers MJ: Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int. 2008 Jun;19(6):733-59. doi: 10.1007/s00198-007-0540-8. [PubMed:18214569]
  6. Murakami H, Takahashi N, Tanaka S, Nakamura I, Udagawa N, Nakajo S, Nakaya K, Abe M, Yuda Y, Konno F, Barbier A, Suda T: Tiludronate inhibits protein tyrosine phosphatase activity in osteoclasts. Bone. 1997 May;20(5):399-404. [PubMed:9145236]
  7. Russell RG: Bisphosphonates: the first 40 years. Bone. 2011 Jul;49(1):2-19. doi: 10.1016/j.bone.2011.04.022. Epub 2011 May 1. [PubMed:21555003]
  8. Health Canada Approved Drug Products: Clodronate Oral Capsules [Link]
Human Metabolome Database
HMDB0014858
PubChem Compound
25419
PubChem Substance
46508646
ChemSpider
23731
BindingDB
50216172
RxNav
3350
ChEBI
110423
ChEMBL
CHEMBL12318
ZINC
ZINC000029747100
Therapeutic Targets Database
DAP000564
PharmGKB
PA10239
Wikipedia
Clodronate
AHFS Codes
  • 92:24.00 — Bone Resorption Inhibitors
MSDS
Download (120 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentBreast Cancer1
3CompletedTreatmentBreast Cancer1
3CompletedTreatmentPain / Prostate Cancer / Quality of Life1
3CompletedTreatmentPostmenopausal Osteoporosis (PMO)1
3CompletedTreatmentRadiation Induced Brachial Plexopathy1
2Unknown StatusTreatmentAseptic Loosening of the Hip Prosthesis1
0CompletedTreatmentOsteoarthritis, Hip1
Not AvailableCompletedNot AvailableBone Neoplasms1
Not AvailableCompletedNot AvailableMultiple Myeloma (MM) / Neoplasms, Breast / Osteolysis / Prostatic Neoplasms1
Not AvailableCompletedNot AvailableOsteoradionecrosis of Jaw1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
SolutionIntravenous
Tablet800 mg
CapsuleOral
CapsuleOral400 MG
Injection, solution, concentrateIntravenous300 MG/10ML
Tablet, film coatedOral800 mg/1
Injection, solutionIntravenous; Parenteral300 MG/10ML
Injection, solutionParenteral100 MG/3.3ML
Injection, solutionIntramuscular100 MG/3.3ML
Injection, solutionIntramuscular200 MG/4ML
Injection, solution, concentrateIntravenous; Parenteral300 MG/10ML
Capsule400 MG
Injection, solution100 MG/3.3ML
Tablet, film coatedOral520 mg
Injection, solution100 MG
Injection, solution300 MG/10ML
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
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

Targets

Kind
Small molecule
Organism
Humans
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]
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
  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
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
  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
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
  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]

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
  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 September 22, 2020 02:11

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