QuickView for Bortezomib (compound)

Summary
General Info

PubChem

PubChem Compound 387447

Name:	bortezomib
PubChem Compound ID:	387447
Molecular formula:	C₁₉H₂₅BN₄O₄
Molecular weight:	384.237 g/mol
Synonyms:	D03150; Velcade (TN); NCI60_029010; MLN-341; Bortezomib (JAN/USAN); Bortezomib; LDP-341; BO2; NSC681239; DPBA. show more » D03150; Velcade (TN); NCI60_029010; MLN-341; Bortezomib (JAN/USAN); Bortezomib; LDP-341; BO2; NSC681239; DPBA; PS-341; Velcade; Pyz-Phe-boroLeu; Boronic acid, [1-[[1-oxo-3-phenyl-2-[(2-pyrazinylcarbonyl) amino]propyl]amino]-3-methylbutyl]-, L-(S)-; AIDS004352; NSC-681239; Boronic acid, [(1(R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]-; LPD-341; Ps 341; 179324-69-7; N-[(1R)-1-(DIHYDROXYBORYL)-3-METHYLBUTYL]-N-(PYRAZIN-2-YLCARBONYL)-L-PHENYLALANINAMIDE; LPD 341; AIDS-004352 show less «

DrugBank

Identification

Name:	bortezomib
Name (isomeric):	DB00188
Drug Type:	small molecule
Brand:	Velcade
Category:	Antineoplastic Agents, Protease Inhibitors
CAS number:	179324-69-7

Pharmacology

Indication:	For treatment of multiple myeloma in patients who have not been successfully treated with at least two previous therapies.
Pharmacology:	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 ... show more » 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. show less «
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 ... show more » 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). show less «
Protein binding:	83% over the concentration range of 100-1000 ng/ml.
Biotransformation:	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

Interactions

Food interaction:

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.

Drug interaction:

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.
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.
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.
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.

Targets

26S proteasome non-ATPase regulatory subunit 2

Proteasome subunit beta type 1

Proteasome subunit beta type 5

Proteasome subunit beta type 2

26S proteasome non-ATPase regulatory subunit 1

Enzymes

Prostaglandin G/H synthase 1

Cytochrome P450 1A1

Cytochrome P450 2C8

Transporters

High affinity copper uptake protein 1