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药品详细

Zoledronate(唑来膦酸)

化学结构式图
中文名
唑来膦酸
英文名
Zoledronate
分子式
C5H10N2O7P2
化学名
[1-hydroxy-2-(1H-imidazol-1-yl)-1-phosphonoethyl]phosphonic acid
分子量
Average: 272.0896
Monoisotopic: 271.996323708
CAS号
118072-93-8
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

Zoledronate (zoledronic acid, marketed by Novartis under the trade names Zometa and Reclast) is a bisphosphonate. Zometa is used to prevent skeletal fractures in patients with cancers such as multiple myeloma and prostate cancer. It can also be used to treat hypercalcemia of malignancy and can be helpful for treating pain from bone metastases.

An annual dose of Zoledronate may also prevent recurring fractures in patients with a previous hip fracture.

Zoledronate is a single 5 mg infusion for the treatment of Paget’s disease of bone. In 2007, the FDA also approved Reclast for the treatment of postmenopausal osteoporosis.

生产厂家
  • Novartis pharmaceuticals corp
封装厂家
参考
Synthesis Reference Not Available
General Reference
  1. Lyles KW, Colon-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen EF, Boonen S: Zoledronic Acid and Clinical Fractures and Mortality after Hip Fracture. N Engl J Med. 2007 Sep 26;. Pubmed
  2. Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P, Trechsel U, Widmer A, Devogelaer JP, Kaufman JM, Jaeger P, Body JJ, Brandi ML, Broell J, Di Micco R, Genazzani AR, Felsenberg D, Happ J, Hooper MJ, Ittner J, Leb G, Mallmin H, Murray T, Ortolani S, Rubinacci A, Saaf M, Samsioe G, Verbruggen L, Meunier PJ: Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med. 2002 Feb 28;346(9):653-61. Pubmed
  3. Durie BG, Katz M, Crowley J: Osteonecrosis of the jaw and bisphosphonates. N Engl J Med. 2005 Jul 7;353(1):99-102; discussion 99-102. 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
  • Imidazoles
  • Heterocyclic compounds
  • Aromatic compounds
  • Phosphinic Acids and Derivatives
  • Bisphosphonates
  • Cyanamides
适应症
药理
Indication For the treatment of hypercalcemia of malignancy. Also for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. In May of 2007, the drug was approved for treatment of Paget’s Disease.
Pharmacodynamics Zoledronate is a bisphosphonic acid which is an inhibitor of osteoclastic bone resorption. Zoledronate is used to prevent osteoporosis and skeletal fractures, particularly in patients with cancers such as multiple myeloma and prostate cancer. It can also be used to treat hypercalcemia, particularly hypercalcemia of malignancy. It can also be helpful for treating pain from bone metastases.
Mechanism of action The action of zoledronate on bone tissue is based partly on its affinity for hydroxyapatite, which is part of the mineral matrix of bone. Zoledronate also targets farnesyl pyrophosphate (FPP) synthase. Nitrogen-containing bisphosphonates such as zoledronate appear to act as analogues of isoprenoid diphosphate lipids, thereby inhibiting FPP synthase, an enzyme in the mevalonate pathway. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and GGPP) that are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins. This activity inhibits osteoclast activity and reduces bone resorption and turnover. In postmenopausal women, it reduces the elevated rate of bone turnover, leading to, on average, a net gain in bone mass.
Absorption Poorly absorbed (oral absorption is about 1% of what intravenous absorption is).
Volume of distribution Not Available
Protein binding Approximately 22% bound in human plasma, independent of the concentration. However, Canadian product information states binding to human plasma protein is approximately 56%.
Metabolism
Zoledronate does not inhibit human P450 enzymes in vitro and does not undergo biotransformation in vivo.
Route of elimination In 64 patients with cancer and bone metastases, on average (± s.d.) 39 ± 16% of the administered zoledronic acid dose was recovered in the urine within 24 hours, with only trace amounts of drug found in urine post-Day 2.
Half life 146 hours
Clearance
  • Renal cl=3.7 +/- 2.0 L/h
Toxicity There is no experience of acute overdose. Two patients received zoledronate (32 mg) over 5 minutes in clinical trials. Neither patient experienced any clinical or laboratory toxicity. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia.
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00107 Zoledronate Pathway SMP00107
理化性质
Properties
State solid
Experimental Properties
Property Value Source
water solubility Sparingly soluble Not Available
logP -4.2 Not Available
Predicted Properties
Property Value Source
water solubility 3.27e+00 g/l ALOGPS
logP -0.93 ALOGPS
logP -3.9 ChemAxon
logS -1.9 ALOGPS
pKa (strongest acidic) 0.66 ChemAxon
pKa (strongest basic) 6.67 ChemAxon
physiological charge -2 ChemAxon
hydrogen acceptor count 8 ChemAxon
hydrogen donor count 5 ChemAxon
polar surface area 153.11 ChemAxon
rotatable bond count 4 ChemAxon
refractivity 52.16 ChemAxon
polarizability 20.1 ChemAxon
药物相互作用
食物相互作用
Not Available

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