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药品详细

Tiludronate(替鲁膦酸盐)

化学结构式图
中文名
替鲁膦酸盐
英文名
Tiludronate
分子式
C7H9ClO6P2S
化学名
{[(4-chlorophenyl)sulfanyl](phosphono)methyl}phosphonic acid
分子量
Average: 318.608
Monoisotopic: 317.928359441
CAS号
89987-06-4
ATC分类
M05B 未知
药物类型
small molecule
阶段
approved
商品名
同义名
基本介绍

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.

生产厂家
  • Sanofi aventis us llc
封装厂家
参考
Synthesis Reference Not Available
General Reference
  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
  2. Rogers MJ: New insights into the molecular mechanisms of action of bisphosphonates. Curr Pharm Des. 2003;9(32):2643-58. Pubmed
  3. Sansom LN, Necciari J, Thiercelin JF: Human pharmacokinetics of tiludronate. Bone. 1995 Nov;17(5 Suppl):479S-483S. Pubmed
剂型
规格
化合物类型
Type small molecule
Classes
  • Bisphosphonates
Substructures
  • Hydroxy Compounds
  • Carboxylic Acids and Derivatives
  • Phosphonic Acids and Derivatives
  • Benzene and Derivatives
  • Aryl Halides
  • Halobenzenes
  • Aromatic compounds
  • Phosphinic Acids and Derivatives
  • Bisphosphonates
适应症
药理
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.
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
理化性质
Properties
State solid
Experimental Properties
Property Value Source
logP -0.6 Not Available
Predicted Properties
Property Value Source
water solubility 6.97e+00 g/l ALOGPS
logP 0.62 ALOGPS
logP 1.32 ChemAxon
logS -1.7 ALOGPS
pKa (strongest acidic) 1.03 ChemAxon
physiological charge -2 ChemAxon
hydrogen acceptor count 6 ChemAxon
hydrogen donor count 4 ChemAxon
polar surface area 115.06 ChemAxon
rotatable bond count 4 ChemAxon
refractivity 65.11 ChemAxon
polarizability 25.37 ChemAxon
药物相互作用
Drug Interaction
Calcium Acetate The divalent cation of oral Calcium Acetate may significantly decrease the absorption of Tiludronate by forming a nonabsorbable chelate. Oral dosing should be separated by at least 2 hours.
Calcium Chloride Calcium salts may decrease the serum concentration of bisphosphonate derivatives. Avoid administration of oral calcium supplements within 2 hours before or after tiludronate/clodronate/etidronate.
Magnesium oxide The divalent cation of oral Magnesium oxide may significantly decrease the absorption of Tiludronate by forming a nonabsorbable chelate. Oral dosing should be separated by at least 2 hours.
Magnesium Sulfate The divalent cation of oral Magnesium sulfate may significantly decrease the absorption of Tiludronate by forming a nonabsorbable chelate. Oral dosing should be separated by at least 2 hours.
食物相互作用
  • 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.

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