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Identification
NameTiludronate
Accession NumberDB01133  (APRD01259)
TypeSmall Molecule
GroupsApproved, Vet Approved
Description

Tiludronate is a bisphosphonate characterized by a (4-chlorophenylthio) group on the carbon atom of the basic P-C-P structure common to all bisphosphonates.

Structure
Thumb
Synonyms
Acide tiludronique
Acido tiludronico
Acidum tiludronicum
Tiludronate
Tiludronic acid
External Identifiers Not Available
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
SkelidNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Tiludronate Disodium
Thumb
  • InChI Key: DKJJVAGXPKPDRL-UHFFFAOYSA-N
  • Monoisotopic Mass: 317.928359441
  • Average Mass: 318.608
DBSALT000411
Categories
UNII6PNS59HP4Y
CAS number89987-06-4
WeightAverage: 318.608
Monoisotopic: 317.928359441
Chemical FormulaC7H9ClO6P2S
InChI KeyInChIKey=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
Taxonomy
DescriptionThis 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.
KingdomOrganic compounds
Super ClassOrganophosphorus compounds
ClassOrganic phosphonic acids and derivatives
Sub ClassBisphosphonates
Direct ParentBisphosphonates
Alternative Parents
Substituents
  • Bisphosphonate
  • Thiophenol ether
  • Alkylarylthioether
  • Halobenzene
  • Chlorobenzene
  • Benzenoid
  • Monocyclic benzene moiety
  • Aryl halide
  • Aryl chloride
  • Organophosphonic acid
  • Sulfenyl compound
  • Thioether
  • Hydrocarbon derivative
  • Organosulfur compound
  • Organochloride
  • Organohalogen compound
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationFor treatment of Paget's disease of bone (osteitis deformans).
PharmacodynamicsTiludronate is a first generation (non-nitrogenous) bisphosphonate in the same family as etidronate and clodronate. Tiludronate affects calcium metabolism and inhibits bone resorption and soft tissue calcification. Of the tiludronate 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.
Mechanism of actionThe bisphosphonate group binds strongly to the bone mineral, hydroxyapatite. This explains the specific pharmacological action of these compounds on mineralized tissues, especially bone. In vitro studies indicate that tiludronate acts primarily on bone through a mechanism that involves inhibition of osteoclastic activity with a probable reduction in the enzymatic and transport processes that lead to resorption of the mineralized matrix. Bone resorption occurs following recruitment, activation, and polarization of osteoclasts. Tiludronate appears to inhibit osteoclasts by at least two mechanisms: disruption of the cytoskeletal ring structure, possibly by inhibition of protein-tyrosine-phosphatase, thus leading to detachment of osteoclasts from the bone surface and the inhibition of the osteoclastic proton pump.
Related Articles
AbsorptionThe mean oral bioavailability in healthy male subjects is 6% after an oral dose equivalent to 400 mg tiludronic acid administered after an overnight fast and 4 hours before a standard breakfast. In single-dose studies, bioavailability was reduced by 90% when an oral dose equivalent to 400 mg tiludronic acid was administered with, or 2 hours after, a standard breakfast compared to the same dose administered after an overnight fast and 4 hours before a standard breakfast.
Volume of distributionNot Available
Protein bindingApproximately 90% bound to human serum protein (mainly albumin) at plasma concentrations between 1 and 10 mg/L.
Metabolism

In vitro, tiludronic acid is not metabolized in human liver microsomes and hepatocytes. There is no evidence that tiludronate is metabolized in humans.

Route of eliminationThe principal route of elimination of tiludronic acid is in the urine.
Half lifeHalf-life in healthy subjects is 50 hours following administration of a 400 mg single oral dose. Half-life in pagetic patients is about 150 hours following administration of 400 mg tiludronate a day for 12 days. In patients with renal insufficiency (creatinine clearance between 11 and 18 mL per minute [mL/min]), half-life is 205 hours from plasma after administration of a single, oral dose equivalent to 400 mg tiludronate.
Clearance
  • renal cl=10 mL/min [IV administration of 20-mg dose]
ToxicityBased on the known action of tiludronate, hypocalcemia is a potential consequence of overdose. In one patient with hypercalcemia of malignancy, intravenous administration of high doses (800 mg/day total dose, 6 mg/kg/day for 2 days) was associated with acute renal failure and death.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage formsNot Available
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)
CA1327009 No1994-02-152011-02-15Canada
US4876248 No1993-01-302010-01-30Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
logP-0.6Not Available
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 RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
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. Murakami H, Takahashi N, Sasaki T, Udagawa N, Tanaka S, Nakamura I, Zhang D, Barbier A, Suda T: A possible mechanism of the specific action of bisphosphonates on osteoclasts: tiludronate preferentially affects polarized osteoclasts having ruffled borders. Bone. 1995 Aug;17(2):137-44. [PubMed:8554921 ]
  2. Rogers MJ: New insights into the molecular mechanisms of action of bisphosphonates. Curr Pharm Des. 2003;9(32):2643-58. [PubMed:14529538 ]
  3. Sansom LN, Necciari J, Thiercelin JF: Human pharmacokinetics of tiludronate. Bone. 1995 Nov;17(5 Suppl):479S-483S. [PubMed:8573422 ]
External Links
ATC CodesM05BA05
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
Acetylsalicylic acidThe serum concentration of Tiludronate can be decreased when it is combined with Acetylsalicylic acid.
Aluminum hydroxideThe serum concentration of Tiludronate can be decreased when it is combined with Aluminum hydroxide.
AmikacinAmikacin may increase the activities of Tiludronate.
ArbekacinArbekacin may increase the activities of Tiludronate.
BevacizumabThe risk or severity of adverse effects can be increased when Bevacizumab is combined with Tiludronate.
Calcium carbonateThe serum concentration of Tiludronate can be decreased when it is combined with Calcium carbonate.
DeferasiroxThe risk or severity of adverse effects can be increased when Tiludronate is combined with Deferasirox.
EsomeprazoleThe therapeutic efficacy of Tiludronate can be decreased when used in combination with Esomeprazole.
FramycetinFramycetin may increase the activities of Tiludronate.
GentamicinGentamicin may increase the activities of Tiludronate.
IndomethacinThe serum concentration of Tiludronate can be increased when it is combined with Indomethacin.
InfliximabThe risk or severity of adverse effects can be increased when Infliximab is combined with Tiludronate.
Iron DextranThe serum concentration of Tiludronate can be decreased when it is combined with Iron Dextran.
KanamycinKanamycin may increase the activities of Tiludronate.
LansoprazoleThe therapeutic efficacy of Tiludronate can be decreased when used in combination with Lansoprazole.
Magnesium oxideThe serum concentration of Tiludronate can be decreased when it is combined with Magnesium oxide.
Magnesium SulfateThe serum concentration of Tiludronate can be decreased when it is combined with Magnesium Sulfate.
NeomycinNeomycin may increase the activities of Tiludronate.
NetilmicinNetilmicin may increase the activities of Tiludronate.
OmeprazoleThe therapeutic efficacy of Tiludronate can be decreased when used in combination with Omeprazole.
PantoprazoleThe therapeutic efficacy of Tiludronate can be decreased when used in combination with Pantoprazole.
RibostamycinRibostamycin may increase the activities of Tiludronate.
SpectinomycinSpectinomycin may increase the activities of Tiludronate.
StreptomycinStreptomycin may increase the activities of Tiludronate.
TobramycinTobramycin may increase the activities of Tiludronate.
Food Interactions
  • Do not take aluminum or magnesium-containing antacids within 2 hours of taking tiludronate.
  • Take on an empty stomach (at least 2 hours before or after meals) with a full glass of plain water. Other beverages may reduce drug absorption.

Targets

Kind
Small molecule
Organism
Human
Pharmacological action
yes
Actions
antagonist
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 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Proton-transporting atpase activity, rotational mechanism
Specific Function:
Catalytic subunit of the peripheral V1 complex of vacuolar ATPase. V-ATPase vacuolar ATPase is responsible for acidifying a variety of intracellular compartments in eukaryotic cells.
Gene Name:
ATP6V1A
Uniprot ID:
P38606
Molecular Weight:
68303.5 Da
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 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Zinc ion binding
Specific Function:
Tyrosine-protein phosphatase which acts as a regulator of endoplasmic reticulum unfolded protein response. Mediates dephosphorylation of EIF2AK3/PERK; inactivating the protein kinase activity of EIF2AK3/PERK. May play an important role in CKII- and p60c-src-induced signal transduction cascades. May regulate the EFNA5-EPHA3 signaling pathway which modulates cell reorganization and cell-cell repu...
Gene Name:
PTPN1
Uniprot ID:
P18031
Molecular Weight:
49966.44 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 ]
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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13