Identification
- Summary
Tiludronic acid is a bisphosphonate used for the treatment of Paget's disease of bone.
- Generic Name
- Tiludronic acid
- DrugBank Accession Number
- DB01133
- Background
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
Structure for Tiludronic acid (DB01133)
- Weight
- Average: 318.608
Monoisotopic: 317.928359441 - Chemical Formula
- C7H9ClO6P2S
- Synonyms
- Acide tiludronique
- Acido tiludronico
- Acidum tiludronicum
- Tiludronate
- Tiludronic acid
- 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
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- Contraindications & Blackbox Warnings
Avoid life-threatening adverse drug eventsImprove clinical decision support with information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events & improve clinical decision support.- 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
Target Actions Organism AHydroxylapatite antagonistbinderHumans AAdenosine triphosphate (ATP) inhibitorHumans UTyrosine-protein phosphatase non-receptor type 12 inhibitorHumans UTyrosine-protein phosphatase non-receptor type 6 inhibitorHumans UReceptor-type tyrosine-protein phosphatase epsilon inhibitorHumans UV-ATPase Subunits inhibitorHumans - 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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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
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbacavir Abacavir may decrease the excretion rate of Tiludronic acid which could result in a higher serum level. Aceclofenac The risk or severity of gastrointestinal bleeding can be increased when Aceclofenac is combined with Tiludronic acid. Acemetacin The risk or severity of gastrointestinal bleeding can be increased when Acemetacin is combined with Tiludronic acid. Acetaminophen Acetaminophen may decrease the excretion rate of Tiludronic acid which could result in a higher serum level. Acetazolamide Acetazolamide may increase the excretion rate of Tiludronic acid which could result in a lower serum level and potentially a reduction in efficacy. Acetylsalicylic acid The serum concentration of Tiludronic acid can be decreased when it is combined with Acetylsalicylic acid. Aclidinium Tiludronic acid may decrease the excretion rate of Aclidinium which could result in a higher serum level. Acrivastine Tiludronic acid may decrease the excretion rate of Acrivastine which could result in a higher serum level. Acyclovir The risk or severity of nephrotoxicity and hypocalcemia can be increased when Acyclovir is combined with Tiludronic acid. Adefovir dipivoxil The risk or severity of nephrotoxicity and hypocalcemia can be increased when Adefovir dipivoxil is combined with Tiludronic acid. 
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- 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
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Ingredient UNII CAS InChI Key Tiludronate Disodium BH6M93CIA0 149845-07-8 SKUHWSDHMJMHIW-UHFFFAOYSA-L - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Skelid Tablet 200 mg/1 Oral Sanofi Aventis 1997-03-07 2012-11-18 US 
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)
- Affected organisms
- Humans and other mammals
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
- Sansom LN, Necciari J, Thiercelin JF: Human pharmacokinetics of tiludronate. Bone. 1995 Nov;17(5 Suppl):479S-483S. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- FDA Approved Drug Products: Skelid Tiludronate Disodium Oral Tablets (Discontinued) [Link]
- External Links
- Human Metabolome Database
- HMDB0015265
- KEGG Compound
- C08141
- PubChem Compound
- 60937
- PubChem Substance
- 46505302
- ChemSpider
- 54905
- BindingDB
- 50442524
- 57230
- ChEBI
- 9598
- ChEMBL
- CHEMBL1350
- ZINC
- ZINC000001531010
- PharmGKB
- PA451688
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Tiludronic_acid
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Terminated Treatment Otospongiosis 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Sanofi-Aventis Inc.
- Dosage Forms
Form Route Strength Tablet Oral Tablet Oral 200 mg/1 - Prices
Unit description Cost Unit Skelid 200 mg tablet 11.47USD tablet DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US4876248 No 1989-10-24 2010-01-30 US CA1327009 No 1994-02-15 2011-02-15 Canada 
Properties
- State
- Solid
- Experimental Properties
Property Value Source logP -3.8 https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020707ap_skelid_statr_clnphrmr.pdf - Predicted Properties
Property Value Source Water Solubility 6.97 mg/mL ALOGPS logP 0.62 ALOGPS logP 1.32 Chemaxon logS -1.7 ALOGPS pKa (Strongest Acidic) 1.03 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 4 Chemaxon Refractivity 65.11 m3·mol-1 Chemaxon Polarizability 25.37 Å3 Chemaxon Number of Rings 1 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption - 0.8821 Blood Brain Barrier + 0.92 Caco-2 permeable - 0.69 P-glycoprotein substrate Non-substrate 0.82 P-glycoprotein inhibitor I Non-inhibitor 0.9497 P-glycoprotein inhibitor II Non-inhibitor 0.9907 Renal organic cation transporter Non-inhibitor 0.9293 CYP450 2C9 substrate Non-substrate 0.7291 CYP450 2D6 substrate Non-substrate 0.8201 CYP450 3A4 substrate Non-substrate 0.7084 CYP450 1A2 substrate Non-inhibitor 0.7348 CYP450 2C9 inhibitor Non-inhibitor 0.7404 CYP450 2D6 inhibitor Non-inhibitor 0.8875 CYP450 2C19 inhibitor Non-inhibitor 0.7287 CYP450 3A4 inhibitor Non-inhibitor 0.8637 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.871 Ames test Non AMES toxic 0.8148 Carcinogenicity Carcinogens 0.509 Biodegradation Not ready biodegradable 0.9882 Rat acute toxicity 2.9059 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.939 hERG inhibition (predictor II) Non-inhibitor 0.9362
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
Targets
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Yes
Antagonist
Binder
References
- 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. [Article]
- 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. [Article]
- 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. [Article]
Yes
Inhibitor
References
- 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. [Article]
- 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
- 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. [Article]
- 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. [Article]
- 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
- 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. [Article]
- 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. [Article]
- 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
- 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. [Article]
- 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. [Article]
- 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
- 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. [Article]
- 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. [Article]
- 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. [Article]
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
- FDA Approved Drug Products: Skelid Tiludronate Disodium Oral Tablets (Discontinued) [Link]
Drug created at June 13, 2005 13:24 / Updated at February 03, 2023 08:14