GEMCITABINE HYDROCHLORIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C9H11F2N3O4.ClH
Molecular Weight	299.659
Optical Activity	UNSPECIFIED
Defined Stereocenters	3 / 3
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

Cl.NC1=NC(=O)N(C=C1)[C@@H]2O[C@H](CO)[C@@H](O)C2(F)F

InChI

InChIKey=OKKDEIYWILRZIA-OSZBKLCCSA-N

InChI=1S/C9H11F2N3O4.ClH/c10-9(11)6(16)4(3-15)18-7(9)14-2-1-5(12)13-8(14)17;/h1-2,4,6-7,15-16H,3H2,(H2,12,13,17);1H/t4-,6-,7-;/m1./s1

HIDE SMILES / InChI

Molecular Formula	ClH
Molecular Weight	36.461
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Molecular Formula	C9H11F2N3O4
Molecular Weight	263.1981
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	3 / 3
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

Gemcitabine is a nucleoside analog used as chemotherapy. It is marketed as Gemzar® by Eli Lilly and Company. Gemcitabine inhibits thymidylate synthetase, leading to inhibition of DNA synthesis and cell death. Gemcitabine is a prodrug so activity occurs as a result of intracellular conversion to two active metabolites, gemcitabine diphosphate and gemcitabine triphosphate by deoxycitidine kinase. Gemcitabine diphosphate also inhibits ribonucleotide reductase, the enzyme responsible for catalyzing synthesis of deoxynucleoside triphosphates required for DNA synthesis. Finally, Gemcitabine triphosphate (diflurorodeoxycytidine triphosphate) competes with endogenous deoxynucleoside triphosphates for incorporation into DNA. Gemcitabine is indicated for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy; metastatic ovarian cancer; inoperable, locally advanced (Stage IIIA or IIIB), or metastatic (Stage IV) non-small cell lung cancer; and locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Ribonucleoside-diphosphate reductase M1 chain 4	Inhibitor 8,297
DNA 278	Inhibitor 8,297
T-24 2	Inhibitor 8,297	3.0 nM [IC50]
CAKI-1 3	Inhibitor 8,297	30.0 nM [IC50]
PANC-1 5	Inhibitor 8,297	10.0 nM [IC50]
MIA PaCa-2 2	Inhibitor 8,297	7.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Advanced ovarian cancer 5	Primary	Approved 8,429	Gemzar
Metastatic breast cancer 6	Primary	Approved 8,429	Gemzar
Pancreatic cancer 97	Primary	Approved 8,429	Gemzar
Non-small cell lung cancer 206	Primary	Approved 8,429	Gemzar

C_max

Value	Dose	Analyte	Population
229 nM	75 mg/m² 1 times / week multiple, intravenous	GEMCITABINE blood	Homo sapiens
263.6 nM	135 mg/m² 1 times / week multiple, intravenous	GEMCITABINE blood	Homo sapiens
292.5 nM	180 mg/m² 1 times / week multiple, intravenous	GEMCITABINE blood	Homo sapiens

AUC

Value	Dose	Analyte	Population
3526.4 nM × h	75 mg/m² 1 times / week multiple, intravenous	GEMCITABINE blood	Homo sapiens
4818.5 nM × h	135 mg/m² 1 times / week multiple, intravenous	GEMCITABINE blood	Homo sapiens
4863.4 nM × h	180 mg/m² 1 times / week multiple, intravenous	GEMCITABINE blood	Homo sapiens

Doses

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Dose	Population	Adverse events
5700 mg/m2 1 times / 2 weeks multiple, intravenous MTD	unhealthy, 55 years (range: 34-71 years) n = 4	Other AEs: Myelosuppression, Paresthesia...
2200 mg/m2 3 times / 4 weeks multiple, intravenous MTD	unhealthy, 58 years (range: 40-77 years) n = 6	Other AEs: Neutropenia, AST increased...
2800 mg/m2 3 times / 4 weeks multiple, intravenous	unhealthy, 58 years (range: 40-77 years) n = 5	DLT: Hepatotoxicity, Neutropenic infection...
1000 mg/m2 3 times / 4 weeks multiple, intravenous Recommended	unhealthy, 74 years n = 1	Disc. AE: Necrosis skin...
800 mg/m2 3 times / 4 weeks multiple, intravenous	unhealthy, adult n = 979	Disc. AE: Myocardial infarction, Cerebrovascular accident...

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AEs

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AE	Significance	Dose	Population
Myelosuppression		5700 mg/m2 1 times / 2 weeks multiple, intravenous MTD	unhealthy, 55 years (range: 34-71 years) n = 4
Paresthesia		5700 mg/m2 1 times / 2 weeks multiple, intravenous MTD	unhealthy, 55 years (range: 34-71 years) n = 4
Rash	severe	5700 mg/m2 1 times / 2 weeks multiple, intravenous MTD	unhealthy, 55 years (range: 34-71 years) n = 4
ALT increased	grade 2, 1 patient	2200 mg/m2 3 times / 4 weeks multiple, intravenous MTD	unhealthy, 58 years (range: 40-77 years) n = 6
AST increased	grade 2, 1 patient	2200 mg/m2 3 times / 4 weeks multiple, intravenous MTD	unhealthy, 58 years (range: 40-77 years) n = 6

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	TK2 3 hCNT1 2 hCNT2 2 hCNT3 2 MRP5 40

Drug as victim

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Target	Modality	Activity
MRP5 40	substrate 3,367	yes
TK2 3	substrate 3,367	yes
hCNT1 2	substrate 3,367	yes
hCNT2 2	substrate 3,367	yes
hCNT3 2	substrate 3,367	yes

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:175901	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:175901
ChemicalBook	CB4438054	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB4438054
MolPort	MolPort-003-987-478	https://www.molport.com/shop/molecule-link/MolPort-003-987-478
Selleck Chemicals	Gemcitabine(Gemzar)	http://www.selleckchem.com/products/Gemcitabine(Gemzar).html
ZINC	ZINC000018279854	http://zinc15.docking.org/substances/ZINC000018279854

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PubMed

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Title	Date	PubMed
Gemcitabine-induced atrial fibrillation: a hitherto unreported manifestation of drug toxicity.	2000 Apr	10847470
Differential transport of cytosine-containing nucleosides by recombinant human concentrative nucleoside transporter protein hCNT1.	2000 Jan-Feb	10772724
Second-line chemotherapy with paclitaxel, cisplatin and gemcitabine in pre-treated sensitive cisplatin-based patients with advanced non-small cell lung cancer.	2000 May-Jun	10928183
Treatment of classical Kaposi's sarcoma with gemcitabine.	2001	11306832
Noncardiogenic pulmonary edema: an unusual and serious complication of anticancer therapy.	2001	11306727

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Patents

Sample Use Guides

In Vivo Use Guide

For intravenous use only. • Ovarian Cancer: 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. (2.1) • Breast Cancer: 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. (2.2) • Non-Small Cell Lung Cancer: 1000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle or 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. (2.3) • Pancreatic Cancer: 1000 mg/m2 over 30 minutes once weekly for the first 7 weeks, then one week rest, then once weekly for 3 weeks of each 28-day cycle

Route of Administration: Intravenous

In Vitro Use Guide

Treatment of PANC-1 cells with gemcitabine (10 nM) increased the percentage of cells in S phase to 60.1±6.0% and reduced the percentage in the G0/G1 phase to 28.7±4.2%

Substance Class	Chemical
Record UNII	U347PV74IL
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

GEMCITABINE HYDROCHLORIDE

Official Name

English

GEMCITABINE HYDROCHLORIDE [MI]

Common Name

English

GEMCITABINE HYDROCHLORIDE [VANDF]

Common Name

English

GEMCITABINE HYDROCHLORIDE [EP MONOGRAPH]

Common Name

English

Gemcitabine hydrochloride [WHO-DD]

Common Name

English

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Classification Tree

Code System

Code

Antimetabolite

NCI_THESAURUS

C1557

Enzyme Inhibitor

NCI_THESAURUS

C2150

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Code System

Code

Type

Description

RXCUI

236234

PRIMARY

RxNorm

FDA UNII

U347PV74IL

PRIMARY

SMS_ID

100000089809

PRIMARY

EVMPD

SUB02324MIG

PRIMARY

CAS

122111-03-9

PRIMARY

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GEMCITABINE .ALPHA.-ANOMER

IMPURITY -> PARENT

Interaction Type:

CHROMATOGRAPHIC PURITY (HPLC/UV)

Qualification:

USP

Amount:

[<0.1] PERCENT PEAK AREA (limits)


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CYTOSINE

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Interaction Type:

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Qualification:

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Amount:

[<0.1] PERCENT PEAK AREA (limits)

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ACTIVE MOIETY

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SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

Doses

AEs

Overview

OverviewOther

Drug as victim

Sourcing

PubMed

Patents

Sample Use Guides

C_max