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Zoledronic acid hydrate (Zoledronate; CGP 42446; CGP42446A; ZOL 446) is potent and semisynthetic bisphosphonate with anti-bone-resorption activity. It induces apoptosis in osteoclasts by inhibiting enzymes of the mevalonate pathway and preventing the isoprenylation of small GTP-binding proteins such as Ras and Rho. Zoledronic acid is a synthetic imidazole bisphosphonate analog of pyrophosphate with anti-bone-resorption activity. As a third-generation bisphosphonate, zoledronic acid binds to hydroxyapatite crystals in the bone matrix, slowing their dissolution and inhibiting the formation and aggregation of these crystals.
| Targets |
Bisphosphonate (BP), with potent anti-resorptive; RANKL
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|---|---|
| ln Vitro |
In osteocyte-like MLO-Y4 cells, zoledronic acid monohydrate (0.1–1 µM; 48 hours) enhances the expression of sclerostin and receptor activator of nuclear factor kB ligand (RANKL) mRNA[2]. The expression of osteoclastogenesis supporting factor from MLO-Y4 cells is increased by zoledronic acid monohydrate[2]. In MLO-Y4 cells, zoledronic acid monohydrate increases the production of RANKL through the IL-6/JAK2/STAT3 pathway[2]. Monohydrate zoledronic acid suppresses osteoclast development and function by modulating the JNK and NF-κB signaling pathways[3]. In MC3T3-E1 cells, zoledronic acid monohydrate (10-100 µM; 1-7 days) significantly lowers viability[4]. In MC3T3-E1 cells, zoledronic acid monohydrate (10-100 µM; 1-7 days) causes apoptosis[4]. Because it induces apoptosis, zoledronic acid monohydrate (10–100 µM; 4 days) reduces cell viability[4]. At concentrations less than 1 µM, zoledronic acid monohydrate inhibits the differentiation and maturation of MC3T3-E1 cells[4].
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| ln Vivo |
For three weeks, zoledronic acid monohydrate (0.05 mg/kg; intraperitoneally; weekly) enhances the density and content of bone mineral[5]. In vivo bone remodeling and osteoclast and osteoblast function are inhibited by zoledronic acid monohydrate (0.5–1 mg/kg; i.p.; weekly; for 3 weeks), which interferes with the mechanical characteristics of bone[5].
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| Cell Assay |
Cell Viability Assay[4]
Cell Types: MC3T3-E1 cells Tested Concentrations: 0.02 µM, 0.1 µM, 1 µM, 10 µM, 100 µM Incubation Duration: 1 day, 3 days, 5 days, 7 days Experimental Results: decreased cells viability at 10 µM and 100 µM. Apoptosis Analysis[4] Cell Types: MC3T3-E1 cells Tested Concentrations: 0.02 µM, 0.1 µM, 1 µM, 10 µM, 100 µM Incubation Duration: 1 days, 4 days, 7 days Experimental Results: Increased the number of early apoptotic cells and late apoptotic or necrotic cells at dose-dependent and time-dependent (high concentrations). Western Blot Analysis[4] Cell Types: MC3T3-E1 cells Tested Concentrations: 0.02 µM, 0.1 µM, 1 µM, 10 µM, 100 µM Incubation Duration: 4 days Experimental Results: Down-regulated the protein level of inactive caspase-3 and up-regulated the protein level of active caspase-3 at the concentrations of 10 and 100 µM. |
| Animal Protocol |
Animal/Disease Models: Fiveweeks old C57BL6 mice[5]
Doses: 0.05 mg/kg, 0.5 mg/kg, 1 mg/kg Route of Administration: intraperitoneal (ip)injection, weekly, for 3 weeks Experimental Results: Inhibited both osteoclast and osteoblasts function and bone remodeling at 0.5 mg/kg and 1 mg/kg. |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation Because no information is available on the use of zoledronic acid during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. However, absorption of zoledronic acid by a breastfed infant is unlikely. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. |
| References |
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| Additional Infomation |
Zoledronic Acid is a synthetic imidazole bisphosphonate analog of pyrophosphate with anti-bone-resorption activity. A third-generation bisphosphonate, zoledronic acid binds to hydroxyapatite crystals in the bone matrix, slowing their dissolution and inhibiting the formation and aggregation of these crystals. This agent also inhibits farnesyl pyrophosphate synthase, an enzyme involved in terpenoid biosynthesis. Inhibition of this enzyme prevents the biosynthesis of isoprenoid lipids, donor substrates of farnesylation and geranylgeranylation during the post-translational modification of small GTPase signalling proteins, which are important in the process of osteoclast turnover. Decreased bone turnover and stabilization of the bone matrix contribute to the analgesic effect of zoledronic acid with respect to painful osteoblastic lesions. The agent also reduces serum calcium concentrations associated with hypercalcemia.
An imidobisphosphonate inhibitor of BONE RESORPTION that is used for the treatment of malignancy-related HYPERCALCEMIA; OSTEITIS DEFORMANS; and OSTEOPOROSIS. Drug Indication Prevention of skeletal-related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumour-induced hypercalcaemia) in adult patients with advanced malignancies involving bone. Treatment of adult patients with tumour-induced hypercalcaemia. Treatment of osteoporosis: , , , in post-menopausal women; , in men; , , , at increased risk of fracture, including those with a recent low-trauma hip fracture. , , Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy in post-menopausal women and in men at increased risk of fracture. , , Treatment of Paget's disease of the bone. , Prevention of skeletal related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumour-induced hypercalcaemia) in adult patients with advanced malignancies involving bone. Treatment of adult patients with tumour-induced hypercalcaemia (TIH). 4 mg / 5 ml and 4 mg / 100 ml: Prevention of skeletal-related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumour-induced hypercalcaemia) in adult patients with advanced malignancies involving bone. Treatment of adult patients with tumour-induced hypercalcaemia (TIH). 5 mg / 100 ml: Treatment of osteoporosis: in post-menopausal women; in men; at increased risk of fracture, including those with a recent low-trauma hip fracture. Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy: in post-menopausal women; in men; at increased risk of fracture. Treatment of Paget's disease of the bone in adults. Prevention of skeletal-related events and treatment of tumour-induced hypercalcaemia. Prevention of skeletal related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumour-induced hypercalcaemia) in adult patients with advanced malignancies involving bone. Treatment of adult patients with tumour-induced hypercalcaemia (TIH). Treatment of osteoporosis: , , , in post-menopausal women; , in men; , , , at increased risk of fracture including those with a recent low-trauma hip fracture. , , Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy: , , , in post-menopausal women; , in men; , , , at increased risk of fracture. , , Treatment of Paget's disease of the bone in adults. , Treatment of osteoporosisin post-menopausal womenin adult menat increased risk of fracture, including those with recent low-trauma hip fracture. Treatment of osteoporosis associated with long-term systemic glucocorticoid therapyin post-menopausal womenin adult menat increased risk of fracture. Treatment of Paget's disease of the bone in adults. Prevention of skeletal related events in patients with advanced malignancies involving bone |
| Molecular Formula |
C5H12N2O8P2
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|---|---|
| Molecular Weight |
290.1
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| Exact Mass |
290.006
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| Elemental Analysis |
C, 22.07; H, 3.70; N, 10.30; O, 41.16; P, 22.77
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| CAS # |
165800-06-6
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| Related CAS # |
Zoledronic Acid;118072-93-8;Zoledronic acid disodium tetrahydrate;165800-07-7; 165800-06-6 (free acid hydrate); 131654-46-1 (disodium); 165800-08-8 (trisodium hydrate); 827573-11-5 (trisodium); 165800-07-7 (disodium hydrate);
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| PubChem CID |
121586
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| Appearance |
White to off-white solid powder
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| Boiling Point |
764ºC at 760 mmHg
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| Melting Point |
245 °C(dec.)
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| Flash Point |
415.8ºC
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| Vapour Pressure |
1.53E-24mmHg at 25°C
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| LogP |
-2.3
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| Hydrogen Bond Donor Count |
6
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
17
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| Complexity |
327
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(N1C=CN=C1)C(P(=O)(O)O)(P(=O)(O)O)O.O
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| InChi Key |
FUXFIVRTGHOMSO-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C5H10N2O7P2.H2O/c8-5(15(9,10)11,16(12,13)14)3-7-2-1-6-4-7;/h1-2,4,8H,3H2,(H2,9,10,11)(H2,12,13,14);1H2
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| Chemical Name |
(1-hydroxy-2-(1H-imidazol-1-yl)ethane-1,1-diyl)diphosphonic acid hydrate
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| Synonyms |
CGP42446; CGP42446A; ZOL446; CGP-42446; CGP-42446A; ZOL-446; CGP 42446; CGP 42446A; ZOL 446; Zoledronate, trade names: Zometa; Zoledronic acid monohydrate; Zoledronic acid (monohydrate); Zometa; Zoledronate monohydrate; (1-Hydroxy-2-(1H-imidazol-1-yl)ethane-1,1-diyl)diphosphonic acid hydrate; Zoledronate hydrate; Reclast.
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
H2O : ~14.29 mg/mL (~49.26 mM)
DMSO :< 1 mg/mL |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 3.33 mg/mL (11.48 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication (<60°C).
(Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.4471 mL | 17.2354 mL | 34.4709 mL | |
| 5 mM | 0.6894 mL | 3.4471 mL | 6.8942 mL | |
| 10 mM | 0.3447 mL | 1.7235 mL | 3.4471 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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