Identification

Name
Tiludronic acid
Accession Number
DB01133
Description

Tiludronate, or (4-chlorophenyl)thio-methylene-1,1-bisphosphonate, is a first generation bisphosphonate similar to etidronic acid and clodronic acid.1,7 These drugs were developed to mimic the action of pyrophosphate, a regulator of calcification and decalcification.1 Tiludronic acid was first described in the literature in 1988 as a potential treatment for Paget's disease of bone.5

Tiludronic acid was granted FDA approval on 7 March 1997.8

Type
Small Molecule
Groups
Approved, Investigational, Vet approved
Structure
Thumb
Weight
Average: 318.608
Monoisotopic: 317.928359441
Chemical Formula
C7H9ClO6P2S
Synonyms
  • Acide tiludronique
  • Acido tiludronico
  • Acidum tiludronicum
  • Tiludronate
External IDs
  • SR 41319
  • SR-41319

Pharmacology

Indication

Tiludronic acid is indicated to treat Paget's disease of bone in patients with serum alkaline phosphatase levels ≥2 times the upper limit of normal, with symptoms, or with risk of future complications.8

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

Tiludronic acid is a bisphosphonate that prevents osteoclasts from resorbing bone.8 The duration of action is quite long due to the slow clearance from the bone, and the therapeutic window is wide.8 Patients should be counselled regarding the risk of upper GI mucosal irritation as well as gastric and duodenal ulcers.8

Mechanism of action

Bisphosphonates are taken into the bone where they bind to hydroxyapatite.8 Bone resorption by osteoclasts causes local acidification, releasing the bisphosphonate, which is taken into the osteoclast by fluid-phase endocytosis.2 Endocytic vesicles become acidified, releasing bisphosphonates into the cytosol of osteoclasts where they act.2

Osteoclasts mediate resorption of bone.4 When osteoclasts bind to bone they form podosomes, ring structures of F-actin.4 Tiludronate inhibits protein-tyrosine-phosphatase, which increases tyrosine phosphorylation, and disrupts podosome formation.4,8 Tiludronic acid also inhibits V-ATPases in the osteoclast, though the exact subunits are unknown, preventing F-actin from forming podosomes.3,6 Disruption of the podosomes causes osteoclasts to detach from bones, preventing bone resorption.4

TargetActionsOrganism
AHydroxylapatite
antagonist
binder
Humans
UTyrosine-protein phosphatase non-receptor type 12
inhibitor
Humans
UTyrosine-protein phosphatase non-receptor type 6
inhibitor
Humans
UReceptor-type tyrosine-protein phosphatase epsilon
inhibitor
Humans
AAdenosine triphosphate (ATP)
inhibitor
Humans
UV-ATPase Subunits
inhibitor
Humans
Absorption

A single 400mg dose of tiludronic acid reaches a Cmax of 3.35±1.07mg/L, with a Tmax of 1.7—0.9h, and and AUC of 27.2±9.0mg*h/L.1 Tiludronic acid has an oral bioavailability of 2-11% with an average of 6%.1

Volume of distribution

The volume of distribution of tiludronic acid is estimated to be between 30L and 60L.1 Due to the unknown clearance rate from bone, this may underestimate the true volume of distribution.1

Protein binding

Tiludronic acid is approximately 90% protein bound in serum.8 It is mostly bound to albumin.8

Metabolism

Tiludronic acid is not metabolized in vitro in human liver microsomes.8

Route of elimination

Tiludronic acid is 60% eliminated in the urine as the unchanged parent drug.8

Half-life

The mean plasma elimination half-life is 150 hours, though the elimination rate from bone is unknown.8 The terminal phase half life is approximately 40h after a single IV dose of 10-30mg.1

Clearance

Tiludronic acid has a renal clearance of 0.68L/h in healthy subjects and 0.47L/h in subjects with Paget's disease.1,8 Approximately 50% of tilurdronic acid binds to bone but the rate of clearance from the bone is unknown.1

Adverse Effects
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Toxicity

Patients experiencing an overdose may present with hypocalcemia.8 Patients given doses of 6mg/kg/day for 2 days have experienced acute renal failure and death.8 Treat overdose with symptomatic and supportive care.8 Dialysis will not be useful for removal of the drug from serum.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
AbacavirAbacavir may decrease the excretion rate of Tiludronic acid which could result in a higher serum level.
AcarboseAcarbose may decrease the excretion rate of Tiludronic acid which could result in a higher serum level.
AceclofenacThe risk or severity of gastrointestinal bleeding can be increased when Aceclofenac is combined with Tiludronic acid.
AcemetacinThe risk or severity of gastrointestinal bleeding can be increased when Acemetacin is combined with Tiludronic acid.
AcetaminophenAcetaminophen may decrease the excretion rate of Tiludronic acid which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Tiludronic acid which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acidThe serum concentration of Tiludronic acid can be decreased when it is combined with Acetylsalicylic acid.
AclidiniumTiludronic acid may decrease the excretion rate of Aclidinium which could result in a higher serum level.
AcrivastineTiludronic acid may decrease the excretion rate of Acrivastine which could result in a higher serum level.
AcyclovirThe risk or severity of nephrotoxicity and hypocalcemia can be increased when Acyclovir is combined with Tiludronic acid.
Additional Data Available
  • Extended Description
    Extended Description

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

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  • 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 at least 2 hours before or after calcium supplements.
  • Take on an empty stomach. Take at least 2 hours before or after meals.
  • Take separate from antacids. Take at least 2 hours before or after antacids. The bioavailability of this medication is significantly reduced when administered with aluminum or magnesium containing antacids.
  • Take with a full glass of water.

Products

Product Ingredients
IngredientUNIICASInChI Key
Tiludronate DisodiumBH6M93CIA0149845-07-8SKUHWSDHMJMHIW-UHFFFAOYSA-L
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
SkelidTablet200 mg/1OralSanofi Aventis1997-03-072012-11-18US 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.

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  • Product Code
    Product Code

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

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Categories

ATC Codes
M05BA05 — Tiludronic 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
Thiophenol ethers / Chlorobenzenes / Alkylarylthioethers / Aryl chlorides / Organic phosphonic acids / Sulfenyl compounds / Organopnictogen compounds / Organophosphorus compounds / Organochlorides / Organic oxides
show 1 more
Substituents
Alkylarylthioether / Aromatic homomonocyclic compound / Aryl chloride / Aryl halide / Aryl thioether / Benzenoid / Bisphosphonate / Chlorobenzene / Halobenzene / Hydrocarbon derivative
show 12 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
organochlorine compound (CHEBI:9598)

Chemical Identifiers

UNII
6PNS59HP4Y
CAS number
89987-06-4
InChI Key
DKJJVAGXPKPDRL-UHFFFAOYSA-N
InChI
InChI=1S/C7H9ClO6P2S/c8-5-1-3-6(4-2-5)17-7(15(9,10)11)16(12,13)14/h1-4,7H,(H2,9,10,11)(H2,12,13,14)
IUPAC Name
{[(4-chlorophenyl)sulfanyl](phosphono)methyl}phosphonic acid
SMILES
OP(O)(=O)C(SC1=CC=C(Cl)C=C1)P(O)(O)=O

References

Synthesis Reference

William Rocco, Sharon M. Laughlin, "Stable pharmaceutical compositions containing tiludronate hydrates and process for producing the pharmaceutical compositions." U.S. Patent US5656288, issued April, 1995.

US5656288
General References
  1. Sansom LN, Necciari J, Thiercelin JF: Human pharmacokinetics of tiludronate. Bone. 1995 Nov;17(5 Suppl):479S-483S. [PubMed:8573422]
  2. 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]
  3. Qin A, Cheng TS, Pavlos NJ, Lin Z, Dai KR, Zheng MH: V-ATPases in osteoclasts: structure, function and potential inhibitors of bone resorption. Int J Biochem Cell Biol. 2012 Sep;44(9):1422-35. doi: 10.1016/j.biocel.2012.05.014. Epub 2012 May 29. [PubMed:22652318]
  4. 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]
  5. Reginster JY, Jeugmans-Huynen AM, Albert A, Denis D, Deroisy R, Lecart MP, Fontaine MA, Collette J, Franchimont P: Biological and clinical assessment of a new bisphosphonate, (chloro-4 phenyl) thiomethylene bisphosphonate, in the treatment of Paget's disease of bone. Bone. 1988;9(6):349-54. doi: 10.1016/8756-3282(88)90115-9. [PubMed:3073800]
  6. Duan X, Yang S, Zhang L, Yang T: V-ATPases and osteoclasts: ambiguous future of V-ATPases inhibitors in osteoporosis. Theranostics. 2018 Oct 26;8(19):5379-5399. doi: 10.7150/thno.28391. eCollection 2018. [PubMed:30555553]
  7. 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]
  8. FDA Approved Drug Products: Skelid Tiludronate Disodium Oral Tablets (Discontinued) [Link]
Human Metabolome Database
HMDB0015265
KEGG Compound
C08141
PubChem Compound
60937
PubChem Substance
46505302
ChemSpider
54905
BindingDB
50442524
RxNav
57230
ChEBI
9598
ChEMBL
CHEMBL1350
ZINC
ZINC000001531010
PharmGKB
PA451688
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Tiludronate

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3TerminatedTreatmentOtospongiosis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Sanofi-Aventis Inc.
Dosage Forms
FormRouteStrength
TabletOral200 mg/1
Prices
Unit descriptionCostUnit
Skelid 200 mg tablet11.47USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US4876248No1989-10-242010-01-30US flag
CA1327009No1994-02-152011-02-15Canada flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
PropertyValueSource
logP-3.8https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020707ap_skelid_statr_clnphrmr.pdf
Predicted Properties
PropertyValueSource
Water Solubility6.97 mg/mLALOGPS
logP0.62ALOGPS
logP1.32ChemAxon
logS-1.7ALOGPS
pKa (Strongest Acidic)1.03ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area115.06 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity65.11 m3·mol-1ChemAxon
Polarizability25.37 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption-0.8821
Blood Brain Barrier+0.92
Caco-2 permeable-0.69
P-glycoprotein substrateNon-substrate0.82
P-glycoprotein inhibitor INon-inhibitor0.9497
P-glycoprotein inhibitor IINon-inhibitor0.9907
Renal organic cation transporterNon-inhibitor0.9293
CYP450 2C9 substrateNon-substrate0.7291
CYP450 2D6 substrateNon-substrate0.8201
CYP450 3A4 substrateNon-substrate0.7084
CYP450 1A2 substrateNon-inhibitor0.7348
CYP450 2C9 inhibitorNon-inhibitor0.7404
CYP450 2D6 inhibitorNon-inhibitor0.8875
CYP450 2C19 inhibitorNon-inhibitor0.7287
CYP450 3A4 inhibitorNon-inhibitor0.8637
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.871
Ames testNon AMES toxic0.8148
CarcinogenicityCarcinogens 0.509
BiodegradationNot ready biodegradable0.9882
Rat acute toxicity2.9059 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.939
hERG inhibition (predictor II)Non-inhibitor0.9362
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
Binder
References
  1. Jahnke W, Henry C: An in vitro assay to measure targeted drug delivery to bone mineral. ChemMedChem. 2010 May 3;5(5):770-6. doi: 10.1002/cmdc.201000016. [PubMed:20209564]
  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]
  3. Drake MT, Clarke BL, Khosla S: Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc. 2008 Sep;83(9):1032-45. doi: 10.4065/83.9.1032. [PubMed:18775204]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Dephosphorylates a range of proteins, and thereby regulates cellular signaling cascades (PubMed:18559503). Dephosphorylates cellular tyrosine kinases, such as ERBB2 and PTK2B/PYK2, and thereby regulates signaling via ERBB2 and PTK2B/PYK2 (PubMed:17329398, PubMed:27134172). Selectively dephosphorylates ERBB2 phosphorylated at 'Tyr-1112', 'Tyr-1196', and/or 'Tyr-1248' (PubMed:27134172).
Specific Function
Non-membrane spanning protein tyrosine phosphatase activity
Gene Name
PTPN12
Uniprot ID
Q05209
Uniprot Name
Tyrosine-protein phosphatase non-receptor type 12
Molecular Weight
88105.665 Da
References
  1. 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]
  2. Sheng MH, Lau KH: Role of protein-tyrosine phosphatases in regulation of osteoclastic activity. Cell Mol Life Sci. 2009 Jun;66(11-12):1946-61. doi: 10.1007/s00018-009-8811-5. [PubMed:19189046]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Modulates signaling by tyrosine phosphorylated cell surface receptors such as KIT and the EGF receptor/EGFR. The SH2 regions may interact with other cellular components to modulate its own phosphatase activity against interacting substrates. Together with MTUS1, induces UBE2V2 expression upon angiotensin II stimulation. Plays a key role in hematopoiesis.
Specific Function
Cell adhesion molecule binding
Gene Name
PTPN6
Uniprot ID
P29350
Uniprot Name
Tyrosine-protein phosphatase non-receptor type 6
Molecular Weight
67560.79 Da
References
  1. 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]
  2. Sheng MH, Lau KH: Role of protein-tyrosine phosphatases in regulation of osteoclastic activity. Cell Mol Life Sci. 2009 Jun;66(11-12):1946-61. doi: 10.1007/s00018-009-8811-5. [PubMed:19189046]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Transmembrane receptor protein tyrosine phosphatase activity
Specific Function
Isoform 1 plays a critical role in signaling transduction pathways and phosphoprotein network topology in red blood cells. May play a role in osteoclast formation and function (By similarity).Isofo...
Gene Name
PTPRE
Uniprot ID
P23469
Uniprot Name
Receptor-type tyrosine-protein phosphatase epsilon
Molecular Weight
80641.165 Da
References
  1. 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]
  2. Sheng MH, Lau KH: Role of protein-tyrosine phosphatases in regulation of osteoclastic activity. Cell Mol Life Sci. 2009 Jun;66(11-12):1946-61. doi: 10.1007/s00018-009-8811-5. [PubMed:19189046]
Kind
Small molecule
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
References
  1. Rogers MJ, Crockett JC, Coxon FP, Monkkonen J: Biochemical and molecular mechanisms of action of bisphosphonates. Bone. 2011 Jul;49(1):34-41. doi: 10.1016/j.bone.2010.11.008. Epub 2010 Nov 26. [PubMed:21111853]
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Required for assembly and activity of the vacuolar ATPase. Potential role in differential targeting and regulation of the enzyme for a specific organelle (By similarity).
Specific Function
Atpase binding

Components:
References
  1. David P, Nguyen H, Barbier A, Baron R: The bisphosphonate tiludronate is a potent inhibitor of the osteoclast vacuolar H(+)-ATPase. J Bone Miner Res. 1996 Oct;11(10):1498-507. [PubMed:8889850]
  2. Qin A, Cheng TS, Pavlos NJ, Lin Z, Dai KR, Zheng MH: V-ATPases in osteoclasts: structure, function and potential inhibitors of bone resorption. Int J Biochem Cell Biol. 2012 Sep;44(9):1422-35. doi: 10.1016/j.biocel.2012.05.014. Epub 2012 May 29. [PubMed:22652318]
  3. Duan X, Yang S, Zhang L, Yang T: V-ATPases and osteoclasts: ambiguous future of V-ATPases inhibitors in osteoporosis. Theranostics. 2018 Oct 26;8(19):5379-5399. doi: 10.7150/thno.28391. eCollection 2018. [PubMed:30555553]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. FDA Approved Drug Products: Skelid Tiludronate Disodium Oral Tablets (Discontinued) [Link]

Drug created on June 13, 2005 07:24 / Updated on July 02, 2020 07:22

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