BENDAMUSTINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C16H21Cl2N3O2
Molecular Weight	358.263
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CN1C(CCCC(O)=O)=NC2=C1C=CC(=C2)N(CCCl)CCCl

InChI

InChIKey=YTKUWDBFDASYHO-UHFFFAOYSA-N

InChI=1S/C16H21Cl2N3O2/c1-20-14-6-5-12(21(9-7-17)10-8-18)11-13(14)19-15(20)3-2-4-16(22)23/h5-6,11H,2-4,7-10H2,1H3,(H,22,23)

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/022249lbl.pdf | https://www.ncbi.nlm.nih.gov/pubmed/22362008

Bendamustine, brand name Treanda, is a chemotherapeutic agent that displays a unique pattern of cytotoxicity compared with conventional alkylating agents. Treanda is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL), in addition Trenda in phase III of clinical trial for the treatment patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Bendamustine is a bifunctional mechlorethamine derivative. Mechlorethamine and its derivatives dissociate into electrophilic alkyl groups. These groups form covalent bonds with electron-rich nucleophilic moieties. The bifunctional covalent linkage can lead to cell death via several pathways. The exact mechanism of action of bendamustine remains unknown. Molecular analyses have revealed that bendamustine differs from other alkylating agents in its mechanism of action. Differences have been observed about its effects on DNA repair and cell cycle progression. Moreover, bendamustine can induce cell death through both apoptotic and nonapoptotic pathways, thereby retaining activity even in cells without a functional apoptotic pathway. Bendamustine possesses the typical adverse reactions for the nitrogen mustards, and include nausea, fatigue, vomiting, diarrhea, fever, constipation, loss of appetite, cough, headache, unintentional weight loss.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
DNA 278 Target ID: CHEMBL2311221 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22362008	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Chronic lymphocytic leukemia 59 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/022249lbl.pdf	Primary		Approved 8429	TREANDA Approved Use TREANDA® (bendamustine hydrochloride) for Injection is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. Launch Date 2008
Non-Hodgkin's lymphoma 79 Sources: https://clinicaltrials.gov/ct2/show/NCT00139841	Primary		Phase III 656	Treanda Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
5.32 μg/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/23322528	120 mg/m² single, intravenous dose: 120 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered:		BENDAMUSTINE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
8797 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/17486132	160 mg/kg single, intravenous dose: 160 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		BENDAMUSTINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
6398 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/23322528	120 mg/m² single, intravenous dose: 120 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered:	BENDAMUSTINE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
444631 ng × min/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/17486132	160 mg/kg single, intravenous dose: 160 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	BENDAMUSTINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
11.17 μg × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/4095129	4.2 mg/kg single, intravenous dose: 4.2 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	BENDAMUSTINE plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
0.65 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/23322528	120 mg/m² single, intravenous dose: 120 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered:	BENDAMUSTINE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
41 min EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/17486132	160 mg/kg single, intravenous dose: 160 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	BENDAMUSTINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
36.1 min EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/4095129	4.2 mg/kg single, intravenous dose: 4.2 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	BENDAMUSTINE plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
5% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208194s000lbl.pdf			BENDAMUSTINE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
100 mg/m2 2 times / 4 weeks steady, intravenous Recommended Dose: 100 mg/m2, 2 times / 4 weeks Route: intravenous Route: steady Dose: 100 mg/m2, 2 times / 4 weeks Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205580s000lbl.pdf	unhealthy, 45-77 years n = 153 Health Status: unhealthy Condition: Chronic Lymphocytic Leukemia Age Group: 45-77 years Sex: M+F Population Size: 153 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205580s000lbl.pdf	Disc. AE: Hypersensitivity, Pyrexia... AEs leading to discontinuation/dose reduction: Hypersensitivity (2%) Pyrexia (1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205580s000lbl.pdf
150 mg/m2 2 times / 4 weeks steady, intravenous Dose: 150 mg/m2, 2 times / 4 weeks Route: intravenous Route: steady Dose: 150 mg/m2, 2 times / 4 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/12756557	unhealthy, 48 years n = 1 Health Status: unhealthy Condition: advanced progressive breast cancer Age Group: 48 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/12756557	Other AEs: Pneumocystis carinii pneumonia... Other AEs: Pneumocystis carinii pneumonia (grade 5, 1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/12756557
280 mg/m2 single, intravenous Highest studied dose Dose: 280 mg/m2 Route: intravenous Route: single Dose: 280 mg/m2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205580s000lbl.pdf	unhealthy, adult n = 4 Health Status: unhealthy Age Group: adult Population Size: 4 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205580s000lbl.pdf	DLT: QT interval prolonged, Sinus tachycardia... Dose limiting toxicities: QT interval prolonged (1 patient) Sinus tachycardia (1 patient) ECG Nonspecific ST-T change (2 patients) Left anterior fascicular block (1 patient) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205580s000lbl.pdf

AEs

AE	Significance	Dose	Population
Pyrexia	1% Disc. AE	100 mg/m2 2 times / 4 weeks steady, intravenous Recommended Dose: 100 mg/m2, 2 times / 4 weeks Route: intravenous Route: steady Dose: 100 mg/m2, 2 times / 4 weeks Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205580s000lbl.pdf	unhealthy, 45-77 years n = 153 Health Status: unhealthy Condition: Chronic Lymphocytic Leukemia Age Group: 45-77 years Sex: M+F Population Size: 153 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205580s000lbl.pdf
Hypersensitivity	2% Disc. AE	100 mg/m2 2 times / 4 weeks steady, intravenous Recommended Dose: 100 mg/m2, 2 times / 4 weeks Route: intravenous Route: steady Dose: 100 mg/m2, 2 times / 4 weeks Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205580s000lbl.pdf	unhealthy, 45-77 years n = 153 Health Status: unhealthy Condition: Chronic Lymphocytic Leukemia Age Group: 45-77 years Sex: M+F Population Size: 153 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205580s000lbl.pdf
Pneumocystis carinii pneumonia	grade 5, 1 patient	150 mg/m2 2 times / 4 weeks steady, intravenous Dose: 150 mg/m2, 2 times / 4 weeks Route: intravenous Route: steady Dose: 150 mg/m2, 2 times / 4 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/12756557	unhealthy, 48 years n = 1 Health Status: unhealthy Condition: advanced progressive breast cancer Age Group: 48 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/12756557
Left anterior fascicular block	1 patient DLT	280 mg/m2 single, intravenous Highest studied dose Dose: 280 mg/m2 Route: intravenous Route: single Dose: 280 mg/m2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205580s000lbl.pdf	unhealthy, adult n = 4 Health Status: unhealthy Age Group: adult Population Size: 4 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205580s000lbl.pdf
QT interval prolonged	1 patient DLT	280 mg/m2 single, intravenous Highest studied dose Dose: 280 mg/m2 Route: intravenous Route: single Dose: 280 mg/m2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205580s000lbl.pdf	unhealthy, adult n = 4 Health Status: unhealthy Age Group: adult Population Size: 4 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205580s000lbl.pdf
Sinus tachycardia	1 patient DLT	280 mg/m2 single, intravenous Highest studied dose Dose: 280 mg/m2 Route: intravenous Route: single Dose: 280 mg/m2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205580s000lbl.pdf	unhealthy, adult n = 4 Health Status: unhealthy Age Group: adult Population Size: 4 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205580s000lbl.pdf
ECG Nonspecific ST-T change	2 patients DLT	280 mg/m2 single, intravenous Highest studied dose Dose: 280 mg/m2 Route: intravenous Route: single Dose: 280 mg/m2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205580s000lbl.pdf	unhealthy, adult n = 4 Health Status: unhealthy Age Group: adult Population Size: 4 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205580s000lbl.pdf

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
		inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2E1 882 CYP3A4/5 278 OAT3 642 OAT1 599 OAT4 146	P-gp 1537 CYP1A2 1054 BCRP 561	CYP 76

Drug as perpetrator

Target	Modality	Activity
OAT1 603	inhibitor 3277 Sources: https://journals.physiology.org/doi/full/10.1152/ajprenal.00467.2014?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org	no
OAT4 146	inhibitor 3277 Sources: https://journals.physiology.org/doi/full/10.1152/ajprenal.00467.2014?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org	no
CYP 147	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/22249s000_MedR_P2.pdf#page=3 Page: 3.0	unlikely
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/22249s000_MedR_P2.pdf#page=3 Page: 3.0	unlikely
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/22249s000_MedR_P2.pdf#page=3 Page: 3.0	unlikely
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/22249s000_MedR_P2.pdf#page=3 Page: 3.0	unlikely
CYP3A4/5 335	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/22249s000_MedR_P2.pdf#page=3 Page: 3.0	unlikely
OAT3 644	inhibitor 3277 Sources: https://journals.physiology.org/doi/full/10.1152/ajprenal.00467.2014?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org	yes [IC50 0.8 uM]

Drug as victim

Target	Modality	Activity	Clinical evidence
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/22249s000_MedR_P2.pdf#page=3 Page: 3.0	likely
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/22249s000_MedR_P2.pdf#page=3 Page: 3.0	likely
CYP1A2 1054	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/22249s000_MedR_P2.pdf#page=3 Page: 3.0	yes	likely (co-administration study) Comment: Inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) have potential to increase plasma concentrations of bendamustine; Inducers of CYP1A2 (e.g., omeprazole, smoking) have potential to decrease plasma concentrations of bendamustine (see label: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/022249lbl.pdf#page=3) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/22249s000_MedR_P2.pdf#page=3 Page: 3.0

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/22249s000_PharmR.pdf#page=52 Page: 52.0

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY530126	https://www.001chemical.com/chem/16506-27-7
3B Scientific (Wuhan) Corp	3B2-1310	http://www.3bsc.com/index/pro_info.php?id=55026
AHH Chemical co.,ltd	MT-47369	http://www.ahhchemical.com/product/MT-47369.html
Aaron Chemicals	AR007VZS	http://www.aaronchem.com/16506-27-7
Acadechem	ACDX-012243	http://acadechemical.com/product/87022
Achemtek	0102-012572	http://www.achemtek.com/16506-27-7
Alfa Chemistry	ACM16506277	https://www.alfa-chemistry.com/bendamustine-cas-16506-27-7-item-1275.htm
Alichem	69004252	http://www.alichem.com/en/products/16506-27-7.html
Alsachim	3205	http://www.alsachim.com/product-C4302-glo.bal-view.html
Ambinter	Amb17942794	http://www.ambinter.com/reference/17942794
Angel Pharmatech	AG309196	http://www.angelpharmatech.com/16506-27-7.html
ApexBio Technology	A1984	http://www.apexbt.com/bendamustine-hcl.html
Aurora Fine Chemicals LLC	A24.073.845	http://online.aurorafinechemicals.com/info?ID=A24.073.845
AvaChem Scientific	2625B	http://www.avachem.com/productSearch.asp?2625B
BLD Pharm	BD115312	http://www.bldpharm.com/products/16506-27-7.html
BOC Sciences	16506-27-7	https://www.bocsci.com/bendamustine-cas-16506-27-7-item-60437.html
BioChemPartner	BCP04111	http://www.biochempartner.com/16506-27-7-BCP04111
BioSynth	J-010179	https://www.biosynth.com/en/products/all-products/products/J-010179.html
Boerchem	BC645220	http://www.boerchem.com/?product_38716.html
Chem Scene	CS-0007192	http://www.chemscene.com/16506-27-7.html
ChemFish Tokyo co.,ltd	65628	http://www.chemfish.co.jp/index.php?id=3771&project=product
ChemMol	30114425	http://www.chemmol.com/chemmol/30114425.html
ChemMol	44012328	http://www.chemmol.com/chemmol/44012328.html
ChemMol	49408640	http://www.chemmol.com/chemmol/49408640.html
Chemspace	CSSB00000054712	https://chem-space.com/CSSB00000054712
Clearsynth	CS-O-00949	https://www.clearsynth.com/en/CSO00949.html
Finetech	FT-0742187	http://www.finetechnology-ind.com/prod/detail/pub/16506-27-7.html
Hairui	HR128613	http://www.hairuichem.com/en/product/16506-27-7.html
Lab Network	LN01345564	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01345564
MedChem Express	HY-13567	https://www.medchemexpress.com/Bendamustine.html
MolPort	MolPort-003-844-702	https://www.molport.com/shop/molecule-link/MolPort-003-844-702
Molcore	MC530126	https://www.molcore.com/product/16506-27-7
OChem	8398	http://www.ocheminc.com/index.php?act=psearch&pid=506B277
Smolecule	S520743	http://www.smolecule.com/products/s520743
Smolecule	S749420	https://www.smolecule.com/products/s749420
THE BioTek	bt-261337	https://www.thebiotek.com/product/inhibitors/bt-261337
THE BioTek	bt-302113	https://www.thebiotek.com/product/others/bt-302113
THE BioTek	bt-459855	https://www.thebiotek.com/product/others/bt-459855
Yuhao Chemical	YH38562	http://www.chemyuhao.com/16506-27-2.html
abcr GmbH	AB461070	http://www.abcr.com/shop/en/AB461070
eNovation Chemicals	D678243	https://www.enovationchem.com/ProductDetails.asp?ProductID=D678243
iChemical	EBD2197491	http://www.ichemical.com/products/16506-27-7.html?utm_source=PubChem&utm_medium=website&utm_campaign=product%20catalogs

PubMed

Title	Date	PubMed
Toxicity of the alkylating agent bendamustin.	1985	3868382
Bendamustine monotherapy in advanced and refractory chronic lymphocytic leukemia.	2001 Jan	11206271
Synergistic effects of chemotherapeutic drugs in lymphoma cells are associated with down-regulation of inhibitor of apoptosis proteins (IAPs), prostate-apoptosis-response-gene 4 (Par-4), death-associated protein (Daxx) and with enforced caspase activation.	2003 Sep 1	12948851
The role of bendamustine in the treatment of indolent non-Hodgkin lymphoma.	2009 Nov 12	21188134
Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis.	2015 May 18	25811541

Patents

Sample Use Guides

In Vivo Use Guide

TREANDA (bendamustine hydrochloride) is intended for administration as an intravenous infusion over 30 minutes. The recommended dose is 100 mg/m2 administered intravenously on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Consider using allopurinol as prevention for patients at high risk of tumor lysis syndrome for the first few weeks of treatment.

Route of Administration: Intravenous

In Vitro Use Guide

Using chronic lymphocytic leukemia (CLL) cells taken from 37 previously treated and untreated CLL patients, was investigated the influence of bendamustine alone, and in combination with fludarabine, on the induction of apoptosis and changes of Bcl-2 and Bax expression on mRNA and protein level. Using bendamustine alone in concentrations from 1 microg/ml to 50 microg/ml, a dose- and time-dependent manner of cytotoxicity from 30.4% to 94.8% after 48 h could be observed. The LD50 for untreated and pretreated CLL cells was 7.3 or 4.4 microg/ml, respectively. The level of the initial Bcl-2 and Bax protein and the m-RNA expression remained unchanged during the incubation with bendamustine.

Name

Type

Language

BENDAMUSTINE

Official Name

English

1H-BENZIMIDAZOLE-2-BUTANOIC ACID, 5-(BIS(2-CHLOROETHYL)AMINO)-1-METHYL-

Common Name

English

BENDAMUSTINE [VANDF]

Common Name

English

BENDAMUSTINE [MI]

Common Name

English

BENDAMUSTINE [HSDB]

Common Name

English

Bendamustine [WHO-DD]

Common Name

English

4-(5-(BIS(2-CHLOROETHYL)AMINO)-1-METHYL-1H-BENZIMIDAZOLE-2-YL)BUTANOIC ACID

Systematic Name

English

bendamustine [INN]

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

584417