Details
| Stereochemistry | ACHIRAL |
| Molecular Formula | 2C7H7ClO6P2S.4Na.H2O |
| Molecular Weight | 743.159 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
O.[Na+].[Na+].[Na+].[Na+].OP([O-])(=O)C(SC1=CC=C(Cl)C=C1)P(O)([O-])=O.OP([O-])(=O)C(SC2=CC=C(Cl)C=C2)P(O)([O-])=O
InChI
InChIKey=KDVKAYPVWJFARG-UHFFFAOYSA-J
InChI=1S/2C7H9ClO6P2S.4Na.H2O/c2*8-5-1-3-6(4-2-5)17-7(15(9,10)11)16(12,13)14;;;;;/h2*1-4,7H,(H2,9,10,11)(H2,12,13,14);;;;;1H2/q;;4*+1;/p-4
| Molecular Formula | Na |
| Molecular Weight | 22.9898 |
| Charge | 1 |
| Count |
|
| Stereochemistry | ACHIRAL |
| Additional Stereochemistry | No |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Optical Activity | NONE |
| Molecular Formula | C7H9ClO6P2S |
| Molecular Weight | 318.608 |
| Charge | 0 |
| Count |
|
| Stereochemistry | ACHIRAL |
| Additional Stereochemistry | No |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Optical Activity | NONE |
| Molecular Formula | HO |
| Molecular Weight | 17.0073 |
| Charge | -1 |
| Count |
|
| Stereochemistry | ACHIRAL |
| Additional Stereochemistry | No |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Optical Activity | NONE |
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. 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. Tiludronic acid is marketed under the tradename Skelid. In vitro studies indicate that tiludronate disodium 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 disodium appears to inhibit osteoclasts through 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. SKELID is indicated for treatment of Paget's disease of bone (osteitis deformans).
Originator
Approval Year
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
1.1 mg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8911885 |
200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
TILUDRONIC ACID plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
|
2.3 mg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8911885 |
400 mg 1 times / day multiple, oral dose: 400 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
TILUDRONIC ACID plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
|
4.7 mg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8911885 |
600 mg 1 times / day multiple, oral dose: 600 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
TILUDRONIC ACID plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
|
7.8 mg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8911885 |
800 mg 1 times / day multiple, oral dose: 800 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
TILUDRONIC ACID plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
10.3 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8911885 |
200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
TILUDRONIC ACID plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
|
25 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8911885 |
400 mg 1 times / day multiple, oral dose: 400 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
TILUDRONIC ACID plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
|
46.8 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8911885 |
600 mg 1 times / day multiple, oral dose: 600 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
TILUDRONIC ACID plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
|
80 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8911885 |
800 mg 1 times / day multiple, oral dose: 800 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
TILUDRONIC ACID plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
78 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8911885 |
400 mg 1 times / day multiple, oral dose: 400 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
TILUDRONIC ACID plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
|
65.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8911885 |
600 mg 1 times / day multiple, oral dose: 600 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
TILUDRONIC ACID plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
|
72 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8911885 |
800 mg 1 times / day multiple, oral dose: 800 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
TILUDRONIC ACID plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
Doses
| Dose | Population | Adverse events |
|---|---|---|
800 mg 1 times / day steady, oral Studied dose Dose: 800 mg, 1 times / day Route: oral Route: steady Dose: 800 mg, 1 times / day Sources: |
healthy, 18 - 45 years n = 10 Health Status: healthy Age Group: 18 - 45 years Sex: M Population Size: 10 Sources: |
|
1200 mg 1 times / day steady, oral Higher than recommended Dose: 1200 mg, 1 times / day Route: oral Route: steady Dose: 1200 mg, 1 times / day Sources: |
unhealthy, 57 - 87 years n = 6 Health Status: unhealthy Condition: Paget's disease of bone Age Group: 57 - 87 years Sex: M+F Population Size: 6 Sources: |
Other AEs: Gastrointestinal disturbance... Other AEs: Gastrointestinal disturbance (3 patients) Sources: |
600 mg 1 times / day steady, oral Studied dose Dose: 600 mg, 1 times / day Route: oral Route: steady Dose: 600 mg, 1 times / day Sources: |
unhealthy, 68 years n = 28 Health Status: unhealthy Condition: Paget's disease of bone Age Group: 68 years Sex: M+F Population Size: 28 Sources: |
DLT: Gastrointestinal symptom NOS... Other AEs: Nausea, Diarrhoea... Dose limiting toxicities: Gastrointestinal symptom NOS (75%) Other AEs:Nausea (7 patients) Sources: Diarrhoea (7 patients) Arthralgia (2 patients) Dyspepsia (5 patients) Skeletal pain (3 patients) Vomiting (6 patients) |
400 mg 1 times / day steady, oral Recommended Dose: 400 mg, 1 times / day Route: oral Route: steady Dose: 400 mg, 1 times / day Sources: |
unhealthy, 72 years n = 29 Health Status: unhealthy Condition: Paget's disease of bone Age Group: 72 years Sex: M+F Population Size: 29 Sources: |
DLT: Gastrointestinal symptom NOS... Dose limiting toxicities: Gastrointestinal symptom NOS (31%) Sources: |
AEs
| AE | Significance | Dose | Population |
|---|---|---|---|
| Gastrointestinal disturbance | 3 patients | 1200 mg 1 times / day steady, oral Higher than recommended Dose: 1200 mg, 1 times / day Route: oral Route: steady Dose: 1200 mg, 1 times / day Sources: |
unhealthy, 57 - 87 years n = 6 Health Status: unhealthy Condition: Paget's disease of bone Age Group: 57 - 87 years Sex: M+F Population Size: 6 Sources: |
| Arthralgia | 2 patients | 600 mg 1 times / day steady, oral Studied dose Dose: 600 mg, 1 times / day Route: oral Route: steady Dose: 600 mg, 1 times / day Sources: |
unhealthy, 68 years n = 28 Health Status: unhealthy Condition: Paget's disease of bone Age Group: 68 years Sex: M+F Population Size: 28 Sources: |
| Skeletal pain | 3 patients | 600 mg 1 times / day steady, oral Studied dose Dose: 600 mg, 1 times / day Route: oral Route: steady Dose: 600 mg, 1 times / day Sources: |
unhealthy, 68 years n = 28 Health Status: unhealthy Condition: Paget's disease of bone Age Group: 68 years Sex: M+F Population Size: 28 Sources: |
| Dyspepsia | 5 patients | 600 mg 1 times / day steady, oral Studied dose Dose: 600 mg, 1 times / day Route: oral Route: steady Dose: 600 mg, 1 times / day Sources: |
unhealthy, 68 years n = 28 Health Status: unhealthy Condition: Paget's disease of bone Age Group: 68 years Sex: M+F Population Size: 28 Sources: |
| Vomiting | 6 patients | 600 mg 1 times / day steady, oral Studied dose Dose: 600 mg, 1 times / day Route: oral Route: steady Dose: 600 mg, 1 times / day Sources: |
unhealthy, 68 years n = 28 Health Status: unhealthy Condition: Paget's disease of bone Age Group: 68 years Sex: M+F Population Size: 28 Sources: |
| Diarrhoea | 7 patients | 600 mg 1 times / day steady, oral Studied dose Dose: 600 mg, 1 times / day Route: oral Route: steady Dose: 600 mg, 1 times / day Sources: |
unhealthy, 68 years n = 28 Health Status: unhealthy Condition: Paget's disease of bone Age Group: 68 years Sex: M+F Population Size: 28 Sources: |
| Nausea | 7 patients | 600 mg 1 times / day steady, oral Studied dose Dose: 600 mg, 1 times / day Route: oral Route: steady Dose: 600 mg, 1 times / day Sources: |
unhealthy, 68 years n = 28 Health Status: unhealthy Condition: Paget's disease of bone Age Group: 68 years Sex: M+F Population Size: 28 Sources: |
| Gastrointestinal symptom NOS | 75% DLT, Disc. AE |
600 mg 1 times / day steady, oral Studied dose Dose: 600 mg, 1 times / day Route: oral Route: steady Dose: 600 mg, 1 times / day Sources: |
unhealthy, 68 years n = 28 Health Status: unhealthy Condition: Paget's disease of bone Age Group: 68 years Sex: M+F Population Size: 28 Sources: |
| Gastrointestinal symptom NOS | 31% DLT, Disc. AE |
400 mg 1 times / day steady, oral Recommended Dose: 400 mg, 1 times / day Route: oral Route: steady Dose: 400 mg, 1 times / day Sources: |
unhealthy, 72 years n = 29 Health Status: unhealthy Condition: Paget's disease of bone Age Group: 72 years Sex: M+F Population Size: 29 Sources: |
PubMed
| Title | Date | PubMed |
|---|---|---|
| A possible mechanism of the specific action of bisphosphonates on osteoclasts: tiludronate preferentially affects polarized osteoclasts having ruffled borders. | 1995 Aug |
|
| Human pharmacokinetics of tiludronate. | 1995 Nov |
|
| Current management strategies for hypercalcemia. | 2003 |
|
| New insights into the molecular mechanisms of action of bisphosphonates. | 2003 |
|
| Drugs in development: bisphosphonates and metalloproteinase inhibitors. | 2003 |
|
| Bisphosphonate resistance in Paget's disease of bone. | 2003 Aug |
|
| Bisphosphonates antagonise bone growth factors' effects on human breast cancer cells survival. | 2003 Jul 7 |
|
| Tiludronate as a new therapeutic agent in the treatment of navicular disease: a double-blind placebo-controlled clinical trial. | 2003 Jun |
|
| Medical treatment of vertebral osteoporosis. | 2003 Oct |
|
| Management of Paget's disease of bone. | 2004 Aug |
|
| Effect of bisphosphonate treatment in patients with Paget's disease of the skull. | 2004 Jan |
|
| Long-term biochemical response after bisphosphonate therapy in Paget's disease of bone. Proposed intervals for monitoring treatment. | 2004 Jul |
|
| Steroid-free medium discloses oestrogenic effects of the bisphosphonate clodronate on breast cancer cells. | 2004 Nov 1 |
|
| In vitro toxicity of bisphosphonates on human neuroblastoma cell lines. | 2004 Sep |
|
| The role of bisphosphonates in the management of advanced cancer with a focus on non-small-cell lung cancer. Part 1: Mechanisms of action, role of biomarkers and preclinical applications. | 2005 |
|
| Non-isomerized C-telopeptide fragments are highly sensitive markers for monitoring disease activity and treatment efficacy in Paget's disease of bone. | 2005 Apr |
|
| [Paget's disease and its therapeutic management]. | 2005 Apr 23 |
|
| Prediction of genotoxicity of chemical compounds by statistical learning methods. | 2005 Jun |
|
| Tiludronate inhibits prostaglandin F2alpha-induced vascular endothelial growth factor synthesis in osteoblasts. | 2005 May 31 |
|
| [Treatment of Paget's disease of bone with zoledronic acid]. | 2005 Nov-Dec |
|
| Comparative effects of antiresorptive agents on bone mineral density and bone turnover in postmenopausal women. | 2006 |
|
| Gateways to clinical trials. | 2006 Apr |
|
| -511 C/T IL1B gene polymorphism is associated to resistance to bisphosphonates treatment in Paget disease of bone. | 2006 Apr |
|
| Medical management of Paget's disease of bone: indications for treatment and review of current therapies. | 2006 Dec |
|
| Biochemical response to bisphosphonate therapy in pagetic patients with skull involvement. | 2006 Jul |
|
| Effects of bisphosphonates on prostaglandin E2 and thromboxane B2 production in human whole blood and monocytes stimulated by lipopolysaccharide and A23187. | 2006 Jul-Aug |
|
| Minodronate suppresses prostaglandin F2alpha-induced vascular endothelial growth factor synthesis in osteoblasts. | 2006 Mar |
|
| Relative binding affinities of bisphosphonates for human bone and relationship to antiresorptive efficacy. | 2006 May |
|
| Management of age-related osteoporosis and prevention of associated fractures. | 2006 Sep |
|
| Efficacy of tiludronate in the treatment of horses with signs of pain associated with osteoarthritic lesions of the thoracolumbar vertebral column. | 2007 Mar |
|
| Treatment with tiludronate has a similar effect to risedronate on Paget's disease activity assessed by bone markers and bone scintigraphy. | 2007 Mar-Apr |
|
| Use of zoledronic acid in the treatment of Paget's disease. | 2007 Oct |
|
| Pharmacological effects of tiludronate in horses after long-term immobilization. | 2007 Sep |
|
| Optimizing dosing frequencies for bisphosphonates in the management of postmenopausal osteoporosis: patient considerations. | 2008 |
|
| Comparative pharmacokinetics of two intravenous administration regimens of tiludronate in healthy adult horses and effects on the bone resorption marker CTX-1. | 2008 Apr |
|
| Treatment of Paget's disease of bone: a survey of clinical practice in Australia. | 2008 Jun |
|
| Determination of bisphosphonate active pharmaceutical ingredients in pharmaceuticals and biological material: a review of analytical methods. | 2008 Nov 4 |
|
| Paget disease of bone: therapeutic options. | 2008 Oct |
|
| Once-yearly zoledronic acid in hip fracture prevention. | 2009 |
|
| Paget's disease 2: exploring diagnosis, management and support strategies. | 2009 Feb 24-Mar 2 |
|
| Bisphosphonates in oncology: evidence for the prevention of skeletal events in patients with bone metastases. | 2009 Sep 21 |
|
| Bisphosphonates: molecular mechanisms of action and effects on bone cells, monocytes and macrophages. | 2010 |
|
| Prolonged unilateral disuse osteopenia 14 years post external fixator removal: a case history and critical review. | 2010 |
|
| Bisphosphonates and risk of atrial fibrillation: a meta-analysis. | 2010 |
|
| Effect of dodecylmaltoside (DDM) on uptake of BCS III compounds, tiludronate and cromolyn, in Caco-2 cells and rat intestine model. | 2010 Apr |
|
| Tiludronate infusion in the treatment of bone spavin: a double blind placebo-controlled trial. | 2010 Jul |
|
| Long-term treatment with bisphosphonates and their safety in postmenopausal osteoporosis. | 2010 Jul 21 |
|
| Five-year follow-up of Japanese patients with Paget's disease of the bone after treatment with low-dose oral alendronate: a case series. | 2010 May 31 |
|
| Bisphosphonate protonation states, conformations, and dynamics on bone mineral probed by solid-state NMR without isotope enrichment. | 2010 Sep |
|
| Arylamino methylene bisphosphonate derivatives as bone seeking matrix metalloproteinase inhibitors. | 2013 Nov 1 |
Sample Use Guides
A single 400-mg daily oral dose of SKELID (Tiludronic acid), taken with 6 to 8 ounces of plain water
only, should be administered for a period of 3 months. Beverages other than plain water
(including mineral water), food (see below), and some medications. Patients should not lie down for at least 30 minutes after taking this medication. SKELID should not be taken within 2 hours of food.
Route of Administration:
Oral
The ability of tiludronate to inhibit proton transport was 5-fold higher in kidney-derived chicken vesicles (IC50 = 1.1 mM) and 10,000-fold higher in vesicles derived from chicken osteoclasts (IC50 = 466 nM). Tiludronate also potently inhibited proton transport in yeast microsomal preparations (IC50 = 3.5 uM) and inhibited the activity of purified yeast V-ATPase.
| Substance Class |
Chemical
Created
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admin
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Edited
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| Record UNII |
39SMX0W5WK
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| Record Status |
Validated (UNII)
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| Record Version |
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-
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m10868
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39SMX0W5WK
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ANHYDROUS->SOLVATE |
