Identification

Name
Tiludronic acid
Accession Number
DB01133  (APRD01259)
Type
Small Molecule
Groups
Approved, Investigational, Vet approved
Description

Tiludronic acid 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
External IDs
SR 41319 / SR-41319
Product Ingredients
IngredientUNIICASInChI Key
Tiludronate DisodiumBH6M93CIA0149845-07-8SKUHWSDHMJMHIW-UHFFFAOYSA-L
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
SkelidTablet200 mg/1OralSanofi Aventis1997-03-072012-11-18Us
International/Other Brands
Skelid
Categories
UNII
6PNS59HP4Y
CAS number
89987-06-4
Weight
Average: 318.608
Monoisotopic: 317.928359441
Chemical Formula
C7H9ClO6P2S
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

Pharmacology

Indication

For treatment of Paget's disease of bone (osteitis deformans).

Pharmacodynamics

Tiludronate 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 action

The 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.

TargetActionsOrganism
AAdenosine triphosphate (ATP)
inhibitor
Human
AHydroxylapatite
antagonist
Human
UV-type proton ATPase catalytic subunit A
inhibitor
Human
UTyrosine-protein phosphatase non-receptor type 1
inhibitor
Human
Absorption

The 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 distribution
Not Available
Protein binding

Approximately 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 elimination

The principal route of elimination of tiludronic acid is in the urine.

Half life

Half-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]
Toxicity

Based 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
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
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.
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.
AdefovirThe risk or severity of nephrotoxicity and hypocalcemia can be increased when Adefovir is combined with Tiludronic acid.
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.

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
Human Metabolome Database
HMDB0015265
KEGG Compound
C08141
PubChem Compound
60937
PubChem Substance
46505302
ChemSpider
54905
BindingDB
50442524
ChEBI
9598
ChEMBL
CHEMBL1350
PharmGKB
PA451688
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Tiludronate
ATC Codes
M05BA05 — Tiludronic acid

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)
US4876248No1989-10-242010-01-30Us
CA1327009No1994-02-152011-02-15Canada

Properties

State
Solid
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 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

Taxonomy

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
Bisphosphonate / Aryl thioether / Thiophenol ether / Chlorobenzene / Halobenzene / Alkylarylthioether / Benzenoid / Aryl chloride / Monocyclic benzene moiety / Aryl halide
show 12 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
organochlorine compound (CHEBI:9598)

Targets

Kind
Small molecule
Organism
Human
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
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
Uniprot Name
V-type proton ATPase catalytic subunit A
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 EI...
Gene Name
PTPN1
Uniprot ID
P18031
Uniprot Name
Tyrosine-protein phosphatase non-receptor type 1
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]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 08:38