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药品详细

Bortezomib(硼替佐米)

化学结构式图
中文名
硼替佐米
英文名
Bortezomib
分子式
C19H25BN4O4
化学名
[(1R)-3-methyl-1-[(2S)-3-phenyl-2-(pyrazin-2-ylformamido)propanamido]butyl]boronic acid
分子量
Average: 384.237
Monoisotopic: 384.196885774
CAS号
179324-69-7
ATC分类
L01X 其它抗肿瘤药
药物类型
small molecule
阶段
approved
商品名
Velcade;
同义名
bortezomib;
基本介绍

Bortezomib (originally PS-341 and marketed as Velcade by Millennium Pharmaceuticals) is the first therapeutic proteasome inhibitor to be tested in humans. It is approved in the U.S. for treating relapsed multiple myeloma and mantle cell lymphoma. In multiple myeloma, complete clinical responses have been obtained in patients with otherwise refractory or rapidly advancing disease.

生产厂家
  • Millennium pharmaceuticals inc
封装厂家
参考
Synthesis Reference Not Available
General Reference
  1. Adams J, Kauffman M: Development of the proteasome inhibitor Velcade (Bortezomib). Cancer Invest. 2004;22(2):304-11. Pubmed
  2. Bonvini P, Zorzi E, Basso G, Rosolen A: Bortezomib-mediated 26S proteasome inhibition causes cell-cycle arrest and induces apoptosis in CD-30+ anaplastic large cell lymphoma. Leukemia. 2007 Apr;21(4):838-42. Epub 2007 Feb 1. Pubmed
  3. Voorhees PM, Dees EC, O’Neil B, Orlowski RZ: The proteasome as a target for cancer therapy. Clin Cancer Res. 2003 Dec 15;9(17):6316-25. Pubmed
  4. Oakervee HE, Popat R, Curry N, Smith P, Morris C, Drake M, Agrawal S, Stec J, Schenkein D, Esseltine DL, Cavenagh JD: PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol. 2005 Jun;129(6):755-62. Pubmed
剂型
规格
化合物类型
Type small molecule
Classes Not Available
Substructures Not Available
适应症
Cancer 癌症;
药理
Indication For treatment of multiple myeloma in patients who have not been successfully treated with at least two previous therapies.
Pharmacodynamics Bortezomib is a drug that inhibits the mammalian 26S proteasome. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro. Bortezomib causes a delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma. Tumor cells, that is, rapidly dividing cells, appear to be more sensitive to proteasome inhibition.
Mechanism of action Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The active site of the proteasome has chymotrypsin-like, trypsin-like, and postglutamyl peptide hydrolysis activity. The 26S proteasome degrades various proteins critical to cancer cell survival, such as cyclins, tumor suppressors, BCL-2, and cyclin-dependent kinase inhibitors. Inhibition of these degradations sensitizes cells to apoptosis. Bortezomib is a potent inhibitor of 26S proteasome, which sensitizes activity in dividing multiple myeloma and leukemic cells, thus inducing apoptosis. In addition, bortezomib appears to increase the sensitivity of cancer cells to traditional anticancer agents (e.g., gemcitabine, cisplatin, paclitaxel, irinotecan, and radiation).
Absorption Not Available
Volume of distribution Not Available
Protein binding 83% over the concentration range of 100-1000 ng/ml.
Metabolism
In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes 3A4, 2C19, and 1A2, while bortezomib metabolism by CYP 2D6 and 2C9 enzymes is minor. The major metabolic pathway is deboronation to form 2 deboronated metabolites that subsequently undergo hydroxylation to several metabolites which are inactive as 26S proteasome inhibitors.
Route of elimination The pathways of elimination of bortezomib have not been characterized in humans.
Half life The mean elimination half-life of bortezomib after first dose ranged from 9 to 15 hours at doses ranging from 1.45 to 2.00 mg/m2 in patients with advanced malignancies.
Clearance
  • 102 L/h [patients with multiple myeloma following the first dose for doses of 1 mg/m2]
  • 112 L/h [patients with multiple myeloma following the first dose for doses of 1.3 mg/m2]
  • 15 – 32 L/h [patients with multiple myeloma following subsequent doses for doses of 1 and 1.3 mg/m2]
Toxicity Cardiovascular safety pharmacology studies in monkeys show that lethal IV doses are associated with decreases in blood pressure, increases in heart rate, increases in contractility, and ultimately terminal hypotension. In monkeys, doses of 3.0 mg/m2 and greater (approximately twice the recommended clinical dose) resulted in progressive hypotension starting at 1 hour and progressing to death by 12 to 14 hours following drug administration.
Affected organisms
  • Humans and other mammals
Pathways Not Available
理化性质
Properties
State solid
Experimental Properties
Property Value Source
water solubility The solubility of bortezomib, as the monomeric boronic acid, is 3.3 to 3.8 mg/mL in a pH range of 2 to 6.5. Not Available
Predicted Properties
Property Value Source
water solubility 5.32e-02 g/l ALOGPS
logP 0.89 ALOGPS
logP 1.53 ChemAxon
logS -3.9 ALOGPS
pKa (strongest acidic) 13.04 ChemAxon
pKa (strongest basic) -0.7 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 6 ChemAxon
hydrogen donor count 4 ChemAxon
polar surface area 124.44 ChemAxon
rotatable bond count 9 ChemAxon
refractivity 99.37 ChemAxon
polarizability 40.48 ChemAxon
药物相互作用
Drug Interaction
Clopidogrel Moderate CYP2C19 Inhibitors like bortezomib may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Avoid concurrent use of moderate CYP2C19 inhibitors with clopidogrel whenever possible. If such a combination must be used, monitor closely for evidence of reduced clinical response to clopidogrel.
Etravirine Bortezombib, when used concomitantly with etravirine, may experience a decrease in serum concentration. It is recommended to avoid this combination.
Telithromycin Telithromycin may reduce clearance of Bortezomib. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Bortezomib if Telithromycin is initiated, discontinued or dose changed.
Ticlopidine Ticlopidine may decrease the metabolism and clearance of Bortezomib. Consider alternate therapy or monitor for adverse/toxic effects of Bortezomib if Ticlopidine is initiated, discontinued or dose changed.
Voriconazole Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of bortezomib by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of bortezomib if voriconazole is initiated, discontinued or dose changed.
食物相互作用
  • Citrus fruits - Patients should avoid taking extra vitamin C (ascorbic acid) supplements and vitamin C-containing multi-vitamins during their bortezomib therapy. Ascorbic Acid may diminish the therapeutic effect of Bortezomib.
  • Green Tea - Green Tea may diminish the antineoplastic effect of Bortezomib. Avoid concurrent use of green tea extract and other green tea products during treatment with bortezomib.

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