Identification

Name
Bortezomib
Accession Number
DB00188
Description

Bortezomib is a dipeptide boronic acid derivative and proteasome inhibitor used to treat multiple myeloma and mantle cell lymphoma. It is a reversible inhibitor of the 26S proteasome, which is a protein complex that degrades ubiquitinated proteins in the ubiquitin-proteasome pathway. Inhibition of 26S proteasome leads to cell cycle arrest and apoptosis of cancer cells.11 While inhibition of the 26S proteasome is the main mechanism of action, multiple mechanisms may involved in the therapeutic action of bortezomib.5

In May 2003, bortezomib became the first anticancer proteasome inhibitor that was approved by the FDA.6 Phase I, II, III, and IV clinical trials are undergoing to investigate the therapeutic efficacy of bortezomib in leukemia, myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis, and solid tumours.7

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 384.237
Monoisotopic: 384.196885774
Chemical Formula
C19H25BN4O4
Synonyms
  • [(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid
  • Bortezomib
  • N-[(1R)-1-(DIHYDROXYBORYL)-3-methylbutyl]-N-(pyrazin-2-ylcarbonyl)-L-phenylalaninamide
External IDs
  • BXCL 101
  • BXCL-101
  • BXCL101
  • LDP 341
  • LDP-341
  • LDP341
  • PS 341
  • PS-341
  • PS341

Pharmacology

Indication

Bortezomib is indicated for the treatment of adult patients with multiple myeloma or mantle cell lymphoma.8

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Bortezomib works to target the ubiquitin-proteasome pathway, an essential molecular pathway that promotes protein degradation and maintains the homeostatic intracellular concentrations of proteins.1 However, there is strong evidence in the literature that the ubiquitin-proteasome pathway is often dysregulated, leading to aberrant pathway signalling. In one study, patient-derived chronic lymphocytic leukemia (CLL) cells contained 3-fold higher levels of chymotrypsin-like proteasome activity than normal lymphocytes, indicating that dysregulation of the ubiquitin-proteasome pathway is implicated in malignant cell transformation.1 By reversibly inhibiting an enzyme involved in the ubiquitin-proteasome pathway, bortezomib prevents the proteasome-mediated proteolysis. Bortezomib exerts a cytotoxic effect on various cancer cell types in vitro. In non-clinical tumour models, including multiple myeloma, bortezomib caused a delay in tumour growth.8

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).

TargetActionsOrganism
AProteasome subunit beta type-5
inhibitor
Humans
AProteasome subunit beta type-1
inhibitor
Humans
Absorption

Following intravenous administration of 1 mg/m2 and 1.3 mg/m2 doses, the mean Cmax of bortezomib were 57 and 112 ng/mL, respectively. In a twice-weekly dosing regimen, the Cmax ranged from 67 to 106 ng/mL at the dose of 1 mg/m2 and 89 to 120 ng/mL for the 1.3 mg/m2 dose. In patients with multiple myeloma, the Cmax of bortezomib followig subcutaneous administration was lower than that of intravenously-administered dose; however, the total systemic exposure of the drug was equivalent for both routes of administration.8 There is a wide interpatient variability in plasma concentrations.11

Volume of distribution

The mean distribution volume of bortezomib ranged from approximately 498 to 1884 L/m2 in patients with multiple myeloma receiving a single- or repeat-dose of 1 mg/m2 or 1.3 mg/m2.8

Protein binding

Over the concentration range of 100 to 1000 ng/mL, bortezomib is about 83% bound to human plasma proteins.8

Metabolism

Bortezomib is primarily metabolized by CYP3A4, CYP2C19, and CYP1A2. CYP2D6 and CYP2C9 are also involved in drug metabolism, but to a smaller extent.8 Oxidative deboronation, which involves the removal of boronic acid from the parent compound, is main metabolic pathway. Metabolites of bortezomib are pharmacologically inactive and more than 30 metabolites have been identified in human and animal studies.6

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Route of elimination

Bortezomib is eliminated by both renal and hepatic routes.6

Half-life

The mean elimination half-life of bortezomib ranged from 40 to 193 hours following a multiple dosing regimen at a 1 mg/m2 dose. The half-life ranged from 76 to 108 hours after multiple dosing of 1.3 mg/m2 bortezomib.8

Clearance

Following the administration of a first dose of 1 mg/m2 and 1.3 mg/m2, the mean mean total body clearances were 102 and 112 L/h, respectively. The clearances were 15 and 32 L/h after the subsequent dose of 1 and 1.3 mg/m2, respectively.8

Adverse Effects
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Toxicity

The Lowest published toxic dose (TDLo) in mouse was 5 mg/kg/14D following intraperitoneal administration of an intermittent dose and 1.6 mg/kg/12D following subcutaneous administration of a continuous dose.10

The therapeutic dose of bortezomib is individualized in each patient to prevent overdose. Fatal outcomes occurred in humans following the administration of more than twice the recommended therapeutic dose of bortezomib. The symptoms from overdose included the acute onset of symptomatic hypotension and thrombocytopenia. As there is no known antidote for bortezomib overdosage, monitoring of vital signs and appropriate supportive care should be initiated when drug overdosage is suspected. In monkeys and dogs, increased heart rate, decreased contractility, hypotension, and death were observed with the intravenous dose as low as two times the recommended clinical dose on a mg/m2 basis. A case of a slight increase in the corrected QT interval leading to death occurred in dog studies.8

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Bortezomib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Bortezomib can be increased when combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Bortezomib.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Bortezomib.
AbirateroneThe serum concentration of Bortezomib can be increased when it is combined with Abiraterone.
AcalabrutinibThe metabolism of Bortezomib can be decreased when combined with Acalabrutinib.
AcebutololThe risk or severity of QTc prolongation can be increased when Bortezomib is combined with Acebutolol.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Bortezomib.
AcetaminophenThe metabolism of Acetaminophen can be increased when combined with Bortezomib.
AcetazolamideThe metabolism of Bortezomib can be decreased when combined with Acetazolamide.
Additional Data Available
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Food Interactions
  • Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum concentration of bortezomib.
  • Exercise caution with grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of bortezomib.
  • Limit foods and supplements high in flavonoids. Flavonoids may interfere with the therapeutic action of this drug. Foods high in flavonoids include green vegetables, fruits, and green tea.
  • Limit foods and supplements high in vitamin C. Vitamin C may interfere with the therapeutic action of this drug. Foods high in vitamin C include citrus fruits and beverages.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Act BortezomibPowder, for solutionIntravenous; SubcutaneousActavis Pharma Company2015-11-17Not applicableCanada flag
BortezomibInjection, powder, lyophilized, for solution3.5 mg/1IntravenousDr.Reddy's Laboratories Inc2019-11-01Not applicableUS flag
BortezomibPowder, for solution3.5 mgIntravenous; SubcutaneousApotex Corporation2019-03-25Not applicableCanada flag
BortezomibInjection, powder, lyophilized, for solution1 mg/1mLIntravenousFresenius Kabi USA, LLC2017-11-06Not applicableUS flag
Bortezomib for InjectionPowder, for solutionIntravenous; SubcutaneousSandoz Canada IncorporatedNot applicableNot applicableCanada flag
Bortezomib for InjectionPowder, for solutionIntravenousJuno Pharmaceuticals Corp.Not applicableNot applicableCanada flag
Bortezomib for InjectionPowder, for solutionIntravenous; SubcutaneousJuno Pharmaceuticals Corp.Not applicableNot applicableCanada flag
Bortezomib for InjectionPowder, for solutionIntravenous; SubcutaneousDr Reddy's Laboratories2017-03-21Not applicableCanada flag
Bortezomib for InjectionPowder, for solutionIntravenous; SubcutaneousAuro Pharma IncNot applicableNot applicableCanada flag
Bortezomib for InjectionPowder, for solutionIntravenous; SubcutaneousPfizer Canada UlcNot applicableNot applicableCanada flag
Additional Data Available
  • Application Number
    Application Number
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    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code
    Available for Purchase

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Bortezomib AccordInjection, powder, for solution3.5 mgIntravenous; SubcutaneousAccord Healthcare Limited2015-07-20Not applicableEU flag
Bortezomib HospiraInjection, powder, for solution3.5 mgIntravenous; SubcutaneousHospira, Inc.2016-07-22Not applicableEU flag
Bortezomib SunInjection, powder, for solution3.5 mgIntravenous; SubcutaneousSun Pharmaceutical Industries (Europe) B.V.2016-07-22Not applicableEU flag
PMS-bortezomibPowder, for solutionIntravenous; SubcutaneousPharmascience Inc2018-06-05Not applicableCanada flag
Taro-bortezomibPowder, for solutionIntravenous; SubcutaneousTaro Pharmaceuticals, Inc.Not applicableNot applicableCanada flag
Additional Data Available
  • Application Number
    Application Number
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  • Product Code
    Product Code
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Categories

ATC Codes
L01XX32 — Bortezomib
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as phenylalanine and derivatives. These are compounds containing phenylalanine or a derivative thereof resulting from reaction of phenylalanine at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Phenylalanine and derivatives
Alternative Parents
N-acyl-alpha amino acids and derivatives / Alpha amino acid amides / Amphetamines and derivatives / Pyrazinecarboxamides / 2-heteroaryl carboxamides / Fatty amides / Heteroaromatic compounds / Secondary carboxylic acid amides / Boronic acids / Organic metalloid salts
show 7 more
Substituents
2-heteroaryl carboxamide / Alkylborane / Alpha-amino acid amide / Amphetamine or derivatives / Aromatic heteromonocyclic compound / Azacycle / Benzenoid / Boronic acid / Boronic acid derivative / Carbonyl group
show 23 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
pyrazines, amino acid amide, L-phenylalanine derivative (CHEBI:52717)

Chemical Identifiers

UNII
69G8BD63PP
CAS number
179324-69-7
InChI Key
GXJABQQUPOEUTA-RDJZCZTQSA-N
InChI
InChI=1S/C19H25BN4O4/c1-13(2)10-17(20(27)28)24-18(25)15(11-14-6-4-3-5-7-14)23-19(26)16-12-21-8-9-22-16/h3-9,12-13,15,17,27-28H,10-11H2,1-2H3,(H,23,26)(H,24,25)/t15-,17-/m0/s1
IUPAC Name
[(1R)-3-methyl-1-[(2S)-3-phenyl-2-(pyrazin-2-ylformamido)propanamido]butyl]boronic acid
SMILES
CC(C)C[[email protected]](NC(=O)[[email protected]](CC1=CC=CC=C1)NC(=O)C1=CN=CC=N1)B(O)O

References

Synthesis Reference

Raghavendracharyulu Venkata Palle, Rajasekhar Kadaboina, Veerendeer Murki, Amarendhar Manda, Nageshwar Gunda, Ramaseshagiri Rao Pulla, Mallesha Hanmanthu, Narasimha Naidu Mopidevi, Suresh Kumar Ramdoss, "BORTEZOMIB AND PROCESS FOR PRODUCING SAME." U.S. Patent US20100226597, issued September 09, 2010.

US20100226597
General References
  1. 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:14695130]
  2. 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:15953001]
  3. Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, Maas J, Pien CS, Prakash S, Elliott PJ: Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res. 1999 Jun 1;59(11):2615-22. [PubMed:10363983]
  4. Berkers CR, Verdoes M, Lichtman E, Fiebiger E, Kessler BM, Anderson KC, Ploegh HL, Ovaa H, Galardy PJ: Activity probe for in vivo profiling of the specificity of proteasome inhibitor bortezomib. Nat Methods. 2005 May;2(5):357-62. Epub 2005 Apr 21. [PubMed:15846363]
  5. Chen D, Frezza M, Schmitt S, Kanwar J, Dou QP: Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives. Curr Cancer Drug Targets. 2011 Mar;11(3):239-53. doi: 10.2174/156800911794519752. [PubMed:21247388]
  6. Schwartz R, Davidson T: Pharmacology, pharmacokinetics, and practical applications of bortezomib. Oncology (Williston Park). 2004 Dec;18(14 Suppl 11):14-21. [PubMed:15688598]
  7. Guedes RA, Aniceto N, Andrade MAP, Salvador JAR, Guedes RC: Chemical Patterns of Proteasome Inhibitors: Lessons Learned from Two Decades of Drug Design. Int J Mol Sci. 2019 Oct 25;20(21). pii: ijms20215326. doi: 10.3390/ijms20215326. [PubMed:31731563]
  8. FDA Approved Drug Products: Bortezomib for Injection, for subcutaneous or intravenous use [Link]
  9. Thermo Fisher Scientific: Bortezomib Safety Data Sheet [Link]
  10. Cayman Chemical: Bortezomib Safety Data Sheet [Link]
  11. BC Cancer: Bortezomib Monograph [Link]
Human Metabolome Database
HMDB0014334
KEGG Drug
D03150
PubChem Compound
387447
PubChem Substance
46508736
ChemSpider
343402
BindingDB
50069989
RxNav
358258
ChEBI
52717
ChEMBL
CHEMBL325041
ZINC
ZINC000169746649
Therapeutic Targets Database
DAP001318
PharmGKB
PA10252
PDBe Ligand
BO2
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Bortezomib
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
PDB Entries
2f16 / 3mg0 / 4fwd / 4qvl / 4qvm / 4qvn / 4qvp / 4qvq / 4qvv / 4qvw
show 16 more
FDA label
Download (199 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentRelapsed and/or Refractory Multiple Myeloma1
4CompletedPreventionTransplantation, Kidney1
4CompletedTreatmentChronic Kidney Disease (CKD) / IgA Nephropathy1
4CompletedTreatmentHLA Sensitization1
4CompletedTreatmentMultiple Myeloma (MM)3
4RecruitingTreatmentHematological Neoplasms1
4RecruitingTreatmentImmunoglobulin Light-Chain Amyloidosis1
4RecruitingTreatmentMultiple Myeloma (MM)1
4RecruitingTreatmentNewly Diagnosed Multiple Myeloma1
4TerminatedTreatmentMultiple Myeloma (MM)1

Pharmacoeconomics

Manufacturers
  • Millennium pharmaceuticals inc
Packagers
  • Ben Venue Laboratories Inc.
  • Janssen-Ortho Inc.
  • Millennium Pharmaceuticals
Dosage Forms
FormRouteStrength
Injection, powder, for solutionParenteral1 mg
Injection, powder, for solutionParenteral2.5 mg
Injection, powder, for solutionParenteral3.5 mg
InjectionIntravenous; Subcutaneous3.5 mg
Injection, solutionIntravenous3.5 mg
Injection, powder, lyophilized, for solution
Injection, powder, lyophilized, for solutionIntravenous; Subcutaneous3.5 mg
Injection, powder, lyophilized, for solutionIntravenous1 mg/1mL
Injection, powder, lyophilized, for solutionIntravenous3.5 mg/1
Injection, powder, for solutionCutaneous3.5 MG
Injection, powder, for solutionIntravenous1 MG
Injection, powder, for solutionIntravenous; Subcutaneous3.5 mg
Injection, solutionParenteral2.5 MG/ML
Powder, for solutionIntravenous
Powder, for solutionIntravenous; Subcutaneous
Injection, powder, lyophilized, for solutionIntravenous; Subcutaneous1 mg
Injection, powder, lyophilized, for solutionIntravenous; Subcutaneous2.5 mg
Injection, powder, lyophilized, for solutionParenteral3.5 mg
Injection, powder, for solution
Injection, powder, for solution3.5 mg
PowderIntravenous; Subcutaneous3.5 mg
Injection, powder, lyophilized, for solutionIntravenous3.5 mg
Injection, powder, for solutionIntravenous1.0 mg
Injection, powder, lyophilized, for solutionIntravenous; Subcutaneous3.5 mg/1
Powder, for solutionIntravenous; Subcutaneous3.5 mg
Prices
Unit descriptionCostUnit
Velcade 3.5 mg vial1590.0USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US6083903No2000-07-042014-10-28US flag
CA2203936No2005-04-122015-10-27Canada flag
US5780454Yes1998-07-142017-11-03US flag
US6958319Yes2005-10-252022-07-25US flag
US6713446Yes2004-03-302022-07-25US flag
US8962572No2015-02-242032-11-03US flag
Additional Data Available
  • Filed On
    Filed On
    Available for Purchase

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)139-143Thermo Fisher Scientific Bortezomib Safety Data Sheet
water solubilityThe 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
PropertyValueSource
Water Solubility0.0532 mg/mLALOGPS
logP0.89ALOGPS
logP1.53ChemAxon
logS-3.9ALOGPS
pKa (Strongest Acidic)13.04ChemAxon
pKa (Strongest Basic)-0.7ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area124.44 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity99.37 m3·mol-1ChemAxon
Polarizability40.48 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption-0.6935
Blood Brain Barrier-0.6533
Caco-2 permeable-0.6576
P-glycoprotein substrateSubstrate0.5909
P-glycoprotein inhibitor INon-inhibitor0.785
P-glycoprotein inhibitor IINon-inhibitor1.0
Renal organic cation transporterNon-inhibitor0.9445
CYP450 2C9 substrateNon-substrate0.7145
CYP450 2D6 substrateSubstrate0.8918
CYP450 3A4 substrateNon-substrate0.5209
CYP450 1A2 substrateNon-inhibitor0.855
CYP450 2C9 inhibitorNon-inhibitor0.8267
CYP450 2D6 inhibitorNon-inhibitor0.9304
CYP450 2C19 inhibitorNon-inhibitor0.8108
CYP450 3A4 inhibitorNon-inhibitor0.7308
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9604
Ames testNon AMES toxic0.7439
CarcinogenicityNon-carcinogens0.8064
BiodegradationNot ready biodegradable0.9943
Rat acute toxicity2.4537 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9936
hERG inhibition (predictor II)Non-inhibitor0.8593
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0a4i-0035900000-122163b342b985220f63
MS/MS Spectrum - , positiveLC-MS/MSsplash10-016r-1397000000-e168634cfe7e1453d742

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Threonine-type endopeptidase activity
Specific Function
The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly ...
Gene Name
PSMB5
Uniprot ID
P28074
Uniprot Name
Proteasome subunit beta type-5
Molecular Weight
28480.01 Da
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Threonine-type endopeptidase activity
Specific Function
The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly ...
Gene Name
PSMB1
Uniprot ID
P20618
Uniprot Name
Proteasome subunit beta type-1
Molecular Weight
26489.09 Da

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Curator comments
There is no time-dependent inhibition of CYP3A4 by bortezomib or its metabolites (Lu et al., 2006).
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Hellmann A, Rule S, Walewski J, Shpilberg O, Feng H, van de Velde H, Patel H, Skee DM, Girgis S, Louw VJ: Effect of cytochrome P450 3A4 inducers on the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib in patients with multiple myeloma or non-Hodgkin's lymphoma. Clin Pharmacokinet. 2011 Dec 1;50(12):781-91. doi: 10.2165/11594410-000000000-00000. [PubMed:22087865]
  2. Zhou W, An G, Jian Y, Guo H, Chen W: Effect of CYP2C19 and CYP3A4 gene polymorphisms on the efficacy of bortezomib-based regimens in patients with multiple myeloma. Oncol Lett. 2015 Aug;10(2):1171-1175. doi: 10.3892/ol.2015.3294. Epub 2015 May 29. [PubMed:26622646]
  3. Pekol T, Daniels JS, Labutti J, Parsons I, Nix D, Baronas E, Hsieh F, Gan LS, Miwa G: Human metabolism of the proteasome inhibitor bortezomib: identification of circulating metabolites. Drug Metab Dispos. 2005 Jun;33(6):771-7. doi: 10.1124/dmd.104.002956. Epub 2005 Mar 11. [PubMed:15764713]
  4. Lu C, Gallegos R, Li P, Xia CQ, Pusalkar S, Uttamsingh V, Nix D, Miwa GT, Gan LS: Investigation of drug-drug interaction potential of bortezomib in vivo in female Sprague-Dawley rats and in vitro in human liver microsomes. Drug Metab Dispos. 2006 Apr;34(4):702-8. doi: 10.1124/dmd.105.008060. Epub 2006 Jan 27. [PubMed:16443666]
  5. FDA Approved Drug Products: Bortezomib for Injection, for subcutaneous or intravenous use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
Curator comments
In an in vitro study, bortezomib and its metabolites M1 and M2 were found to be mild inhibitors of CYP2C19 with IC50 values of approximately 18.0, 10.0, and 13.2 microM, respectively (Lu et al., 2006).
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014]
  2. Pekol T, Daniels JS, Labutti J, Parsons I, Nix D, Baronas E, Hsieh F, Gan LS, Miwa G: Human metabolism of the proteasome inhibitor bortezomib: identification of circulating metabolites. Drug Metab Dispos. 2005 Jun;33(6):771-7. doi: 10.1124/dmd.104.002956. Epub 2005 Mar 11. [PubMed:15764713]
  3. Uttamsingh V, Lu C, Miwa G, Gan LS: Relative contributions of the five major human cytochromes P450, 1A2, 2C9, 2C19, 2D6, and 3A4, to the hepatic metabolism of the proteasome inhibitor bortezomib. Drug Metab Dispos. 2005 Nov;33(11):1723-8. doi: 10.1124/dmd.105.005710. Epub 2005 Aug 15. [PubMed:16103134]
  4. Lu C, Gallegos R, Li P, Xia CQ, Pusalkar S, Uttamsingh V, Nix D, Miwa GT, Gan LS: Investigation of drug-drug interaction potential of bortezomib in vivo in female Sprague-Dawley rats and in vitro in human liver microsomes. Drug Metab Dispos. 2006 Apr;34(4):702-8. doi: 10.1124/dmd.105.008060. Epub 2006 Jan 27. [PubMed:16443666]
  5. FDA Approved Drug Products: Bortezomib for Injection, for subcutaneous or intravenous use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014]
  2. Uttamsingh V, Lu C, Miwa G, Gan LS: Relative contributions of the five major human cytochromes P450, 1A2, 2C9, 2C19, 2D6, and 3A4, to the hepatic metabolism of the proteasome inhibitor bortezomib. Drug Metab Dispos. 2005 Nov;33(11):1723-8. doi: 10.1124/dmd.105.005710. Epub 2005 Aug 15. [PubMed:16103134]
  3. Pekol T, Daniels JS, Labutti J, Parsons I, Nix D, Baronas E, Hsieh F, Gan LS, Miwa G: Human metabolism of the proteasome inhibitor bortezomib: identification of circulating metabolites. Drug Metab Dispos. 2005 Jun;33(6):771-7. doi: 10.1124/dmd.104.002956. Epub 2005 Mar 11. [PubMed:15764713]
  4. FDA Approved Drug Products: Bortezomib for Injection, for subcutaneous or intravenous use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Pekol T, Daniels JS, Labutti J, Parsons I, Nix D, Baronas E, Hsieh F, Gan LS, Miwa G: Human metabolism of the proteasome inhibitor bortezomib: identification of circulating metabolites. Drug Metab Dispos. 2005 Jun;33(6):771-7. doi: 10.1124/dmd.104.002956. Epub 2005 Mar 11. [PubMed:15764713]
  2. FDA Approved Drug Products: Bortezomib for Injection, for subcutaneous or intravenous use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
Curator comments
In an in vitro study, the M1 metabolite of bortezomib was a mild inhibitor of CYP2C9 with an IC50 value of approximately 11.5 microM (Lu et al., 2006).
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Pekol T, Daniels JS, Labutti J, Parsons I, Nix D, Baronas E, Hsieh F, Gan LS, Miwa G: Human metabolism of the proteasome inhibitor bortezomib: identification of circulating metabolites. Drug Metab Dispos. 2005 Jun;33(6):771-7. doi: 10.1124/dmd.104.002956. Epub 2005 Mar 11. [PubMed:15764713]
  2. Lu C, Gallegos R, Li P, Xia CQ, Pusalkar S, Uttamsingh V, Nix D, Miwa GT, Gan LS: Investigation of drug-drug interaction potential of bortezomib in vivo in female Sprague-Dawley rats and in vitro in human liver microsomes. Drug Metab Dispos. 2006 Apr;34(4):702-8. doi: 10.1124/dmd.105.008060. Epub 2006 Jan 27. [PubMed:16443666]
  3. Uttamsingh V, Lu C, Miwa G, Gan LS: Relative contributions of the five major human cytochromes P450, 1A2, 2C9, 2C19, 2D6, and 3A4, to the hepatic metabolism of the proteasome inhibitor bortezomib. Drug Metab Dispos. 2005 Nov;33(11):1723-8. doi: 10.1124/dmd.105.005710. Epub 2005 Aug 15. [PubMed:16103134]
  4. FDA Approved Drug Products: Bortezomib for Injection, for subcutaneous or intravenous use [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. O'Connor R, Ooi MG, Meiller J, Jakubikova J, Klippel S, Delmore J, Richardson P, Anderson K, Clynes M, Mitsiades CS, O'Gorman P: The interaction of bortezomib with multidrug transporters: implications for therapeutic applications in advanced multiple myeloma and other neoplasias. Cancer Chemother Pharmacol. 2013 May;71(5):1357-68. doi: 10.1007/s00280-013-2136-7. Epub 2013 Apr 16. [PubMed:23589314]
  2. Clemens J, Welti L, Schafer J, Seckinger A, Burhenne J, Theile D, Weiss J: Bortezomib, carfilzomib and ixazomib do not mediate relevant transporter-based drug-drug interactions. Oncol Lett. 2017 Sep;14(3):3185-3192. doi: 10.3892/ol.2017.6560. Epub 2017 Jul 8. [PubMed:28927064]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
References
  1. Alam K, Farasyn T, Crowe A, Ding K, Yue W: Treatment with proteasome inhibitor bortezomib decreases organic anion transporting polypeptide (OATP) 1B3-mediated transport in a substrate-dependent manner. PLoS One. 2017 Nov 6;12(11):e0186924. doi: 10.1371/journal.pone.0186924. eCollection 2017. [PubMed:29107984]

Drug created on June 13, 2005 07:24 / Updated on November 30, 2020 13:38

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