Tiludronic acid (original) (raw)

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Description

A medication used to treat a type of bone disease that causes abnormal breakdown and weakness of bones.

Description

A medication used to treat a type of bone disease that causes abnormal breakdown and weakness of bones.

DrugBank ID

DB01133

Type

Small Molecule

US Approved

YES

Other Approved

NO

Therapeutic Categories

• Bisphosphonates

Mechanism of Action

• Hydroxylapatite
  Antagonist
  Binder
• Adenosine triphosphate (ATP)
  Inhibitor

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

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

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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Associated Conditions

Contraindications & Blackbox Warnings

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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

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

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

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.

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Product Ingredients

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Skelid	Tablet	200 mg/1	Oral	Sanofi Aventis Deutschland Gmb H	1997-03-07	2012-11-18

ATC Codes

M05BA05 — Tiludronic acid

• M05BA — Bisphosphonates
• M05B — DRUGS AFFECTING BONE STRUCTURE AND MINERALIZATION
• M05 — DRUGS FOR TREATMENT OF BONE DISEASES
• M — MUSCULO-SKELETAL SYSTEM

Drug Categories

• Bisphosphonates
• Bone Density Conservation Agents
• Drugs Affecting Bone Structure and Mineralization
• Drugs for Treatment of Bone Diseases
• Drugs that are Mainly Renally Excreted
• Musculo-Skeletal System
• Organophosphonates
• Organophosphorus Compounds
• Phospholipases A, antagonists & inhibitors

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 / Hydrocarbon derivatives show 1 more

Substituents

Alkylarylthioether / Aromatic homomonocyclic compound / Aryl chloride / Aryl halide / Aryl thioether / Benzenoid / Bisphosphonate / Chlorobenzene / Halobenzene / Hydrocarbon derivative / Monocyclic benzene moiety / Organic oxide / Organic oxygen compound / Organochloride / Organohalogen compound / Organophosphonic acid / Organophosphorus compound / Organopnictogen compound / Organosulfur compound / Sulfenyl compound / Thioether / Thiophenol ether show 12 more

Molecular Framework

Aromatic homomonocyclic compounds

External Descriptors

organochlorine compound (CHEBI:9598)

Affected organisms

• Humans and other mammals

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

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. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
8. 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

RxNav

57230

ChEBI

9598

ChEMBL

CHEMBL1350

ZINC

ZINC000001531010

PharmGKB

PA451688

RxList

RxList Drug Page

Drugs.com

Drugs.com Drug Page

Wikipedia

Tiludronic_acid

Clinical Trials

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View Sample Data

Manufacturers

Not Available

Packagers

• Sanofi-Aventis Inc.

Dosage Forms

Prices

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
CA1327009	No	1994-02-15	2011-02-15

State

Solid

Experimental Properties

Predicted Properties

Predicted ADMET Features

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Mass Spec (NIST)

Not Available

Spectra

Chromatographic Properties

Collision Cross Sections (CCS)

Targets

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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. [Article]
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. [Article]
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. [Article]

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. [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

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. [Article]
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. [Article]

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

General Function

Tyrosine phosphatase enzyme that plays important roles in controlling immune signaling pathways and fundamental physiological processes such as hematopoiesis (PubMed:29925997). Dephosphorylates and negatively regulate several receptor tyrosine kinases (RTKs) such as EGFR, PDGFR and FGFR, thereby modulating their signaling activities (PubMed:9733788, PubMed:21258366). When recruited to immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptors such as immunoglobulin-like transcript 2/LILRB1, programmed cell death protein 1/PDCD1, CD3D, CD22 and other receptors involved in immune regulation, initiates their dephosphorylation and subsequently inhibits downstream signaling events (PubMed:11907092, PubMed:37932456, PubMed:38166031). Modulates the signaling of several cytokine receptors including IL-4 receptor (PubMed:9065461). Additionally, targets multiple cytoplasmic signaling molecules including STING1, LCK or STAT1 among others involved in diverse cellular processes including modulation of T-cell activation or cGAS-STING signaling (PubMed:34811497, PubMed:38532423). Within the nucleus, negatively regulates the activity of some transcription factors such as NFAT5 via direct dephosphorylation. Acts also as a key transcriptional regulator of hepatic gluconeogenesis by controlling recruitment of RNA polymerase II to the PCK1 promoter together with STAT5A (PubMed:37595871)

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. [Article]
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. [Article]

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

General 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)

Specific Function

protein tyrosine phosphatase activity

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. [Article]
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. [Article]

Kind

Protein group

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

General Function

Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that transports protons across cellular membranes. V-ATPase is responsible for the acidification of various organelles, such as lysosomes, endosomes, the trans-Golgi network, and secretory granules, including synaptic vesicles (PubMed:33065002, PubMed:33833240, PubMed:34909687). In certain cell types, can be exported to the plasma membrane, where it is involved in the acidification of the extracellular environment (By similarity). Required for assembly and activity of the vacuolar ATPase (By similarity). Through its action on compartment acidification, plays an essential role in neuronal development in terms of integrity and connectivity of neurons (PubMed:33833240)

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. [Article]
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. [Article]
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. [Article]

Carriers

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Binder

General Function

Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)

Specific Function

antioxidant activity

Gene Name

ALB

Uniprot ID

P02768

Uniprot Name

Albumin

Molecular Weight

69365.94 Da

References

1. FDA Approved Drug Products: Skelid Tiludronate Disodium Oral Tablets (Discontinued) [Link]

Drug created at June 13, 2005 13:24 / Updated at November 11, 2024 11:16