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

Structure Search

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

Description
Sources: http://www.drugbank.ca/drugs/DB00441
Curator's Comment: Description was created based on several sources, including http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020509s075lbl.pdf

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 Target ID: CHEMBL1830 Sources: http://www.drugbank.ca/drugs/DB00441	Inhibitor 8297
DNA 278 Target ID: DNA Sources: http://www.drugbank.ca/drugs/DB00441	Inhibitor 8297
T-24 2 Target ID: CHEMBL614774 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25833690	Inhibitor 8297	3.0 nM [IC50]
CAKI-1 3 Target ID: CHEMBL614067 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25833690	Inhibitor 8297	30.0 nM [IC50]
PANC-1 5 Target ID: CHEMBL614139 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25517919	Inhibitor 8297	10.0 nM [IC50]
MIA PaCa-2 2 Target ID: CHEMBL614725 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25517919	Inhibitor 8297	7.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Advanced ovarian cancer 5 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020509s075lbl.pdf	Primary	Approved 8429	Gemzar Approved Use Gemzar is a nucleoside metabolic inhibitor indicated: • in combination with carboplatin, for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum- based therapy. • in combination with paclitaxel, for first-line treatment of metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated. • in combination with cisplatin for the treatment of non-small cell lung cancer. • as a single agent for the treatment of pancreatic cancer. Launch Date 1996
Metastatic breast cancer 6 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020509s075lbl.pdf	Primary	Approved 8429	Gemzar Approved Use Gemzar is a nucleoside metabolic inhibitor indicated: • in combination with carboplatin, for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum- based therapy. • in combination with paclitaxel, for first-line treatment of metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated. • in combination with cisplatin for the treatment of non-small cell lung cancer. • as a single agent for the treatment of pancreatic cancer. Launch Date 1996
Pancreatic cancer 97 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020509s075lbl.pdf	Primary	Approved 8429	Gemzar Approved Use Gemzar is a nucleoside metabolic inhibitor indicated: • in combination with carboplatin, for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum- based therapy. • in combination with paclitaxel, for first-line treatment of metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated. • in combination with cisplatin for the treatment of non-small cell lung cancer. • as a single agent for the treatment of pancreatic cancer. Launch Date 1996
Non-small cell lung cancer 206 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020509s075lbl.pdf	Primary	Approved 8429	Gemzar Approved Use Gemzar is a nucleoside metabolic inhibitor indicated: • in combination with carboplatin, for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum- based therapy. • in combination with paclitaxel, for first-line treatment of metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated. • in combination with cisplatin for the treatment of non-small cell lung cancer. • as a single agent for the treatment of pancreatic cancer. Launch Date 1996

C_max

Value	Dose	Analyte	Population
229 nM EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/19556122	75 mg/m² 1 times / week multiple, intravenous dose: 75 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	GEMCITABINE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
263.6 nM EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/19556122	135 mg/m² 1 times / week multiple, intravenous dose: 135 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	GEMCITABINE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
292.5 nM EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/19556122	180 mg/m² 1 times / week multiple, intravenous dose: 180 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	GEMCITABINE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
3526.4 nM × h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/19556122	75 mg/m² 1 times / week multiple, intravenous dose: 75 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	GEMCITABINE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
4818.5 nM × h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/19556122	135 mg/m² 1 times / week multiple, intravenous dose: 135 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	GEMCITABINE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
4863.4 nM × h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/19556122	180 mg/m² 1 times / week multiple, intravenous dose: 180 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	GEMCITABINE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
5700 mg/m2 1 times / 2 weeks multiple, intravenous MTD Dose: 5700 mg/m2, 1 times / 2 weeks Route: intravenous Route: multiple Dose: 5700 mg/m2, 1 times / 2 weeks Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020509s082lbl.pdf https://pubmed.ncbi.nlm.nih.gov/17434832	unhealthy, 55 years (range: 34-71 years) n = 4 Health Status: unhealthy Age Group: 55 years (range: 34-71 years) Sex: M+F Population Size: 4 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020509s082lbl.pdf https://pubmed.ncbi.nlm.nih.gov/17434832	Other AEs: Myelosuppression, Paresthesia... Other AEs: Myelosuppression Paresthesia Rash (severe) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020509s082lbl.pdf https://pubmed.ncbi.nlm.nih.gov/17434832
2200 mg/m2 3 times / 4 weeks multiple, intravenous MTD Dose: 2200 mg/m2, 3 times / 4 weeks Route: intravenous Route: multiple Dose: 2200 mg/m2, 3 times / 4 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/8996158	unhealthy, 58 years (range: 40-77 years) n = 6 Health Status: unhealthy Condition: Non-Small-Cell Lung Cancer Age Group: 58 years (range: 40-77 years) Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/8996158	Other AEs: Neutropenia, AST increased... Other AEs: Neutropenia (grade 2, 1 patient) AST increased (grade 2, 1 patient) ALT increased (grade 2, 1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/8996158
2800 mg/m2 3 times / 4 weeks multiple, intravenous Dose: 2800 mg/m2, 3 times / 4 weeks Route: intravenous Route: multiple Dose: 2800 mg/m2, 3 times / 4 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/8996158	unhealthy, 58 years (range: 40-77 years) n = 5 Health Status: unhealthy Condition: Non-Small-Cell Lung Cancer Age Group: 58 years (range: 40-77 years) Sex: M+F Population Size: 5 Sources: https://pubmed.ncbi.nlm.nih.gov/8996158	DLT: Hepatotoxicity, Neutropenic infection... Dose limiting toxicities: Hepatotoxicity (grade 3, 2 patients) Neutropenic infection (grade 4, 1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/8996158
1000 mg/m2 3 times / 4 weeks multiple, intravenous Recommended Dose: 1000 mg/m2, 3 times / 4 weeks Route: intravenous Route: multiple Dose: 1000 mg/m2, 3 times / 4 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/30397477	unhealthy, 74 years n = 1 Health Status: unhealthy Age Group: 74 years Sex: M Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/30397477	Disc. AE: Necrosis skin... AEs leading to discontinuation/dose reduction: Necrosis skin (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/30397477
800 mg/m2 3 times / 4 weeks multiple, intravenous Dose: 800 mg/m2, 3 times / 4 weeks Route: intravenous Route: multiple Dose: 800 mg/m2, 3 times / 4 weeks Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020509s082lbl.pdf	unhealthy, adult n = 979 Health Status: unhealthy Condition: malignancies Age Group: adult Sex: M+F Population Size: 979 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020509s082lbl.pdf	Disc. AE: Myocardial infarction, Cerebrovascular accident... AEs leading to discontinuation/dose reduction: Myocardial infarction (2%) Cerebrovascular accident (2%) Arrhythmia (2%) Hypertension (2%) Anemia (<1%) Thrombocytopenia (<1%) Hepatic dysfunction NOS (<1%) Kidney dysfunction (<1%) Nausea (<1%) Vomiting (<1%) Fever (<1%) Rash (<1%) Dyspnea (<1%) Hemorrhage (<1%) Infection (<1%) Stomatitis (<1%) Somnolence (<1%) Flu syndrome (<1%) Edema (<1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020509s082lbl.pdf

AEs

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

Target	Modality	Activity
MRP5 40	substrate 3367 Sources: https://www.nature.com/articles/6601011/ Page: -	yes
TK2 3	substrate 3367 Sources: https://www.sciencedirect.com/science/article/pii/S0923753419381785 Page: -	yes
hCNT1 2	substrate 3367 Sources: https://www.sciencedirect.com/science/article/pii/S0923753419381785 Page: -	yes
hCNT2 2	substrate 3367 Sources: https://www.sciencedirect.com/science/article/pii/S0923753419381785 Page: -	yes
hCNT3 2	substrate 3367 Sources: https://www.sciencedirect.com/science/article/pii/S0923753419381785 Page: -	yes

Sourcing

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

PubMed

Title	Date	PubMed
Phase I study of paclitaxel and day 1/day 8 gemcitabine in patients with solid malignancies.	2000 Aug	10955861
Paclitaxel, cisplatin, and gemcitabine combination chemotherapy within a multidisciplinary therapeutic approach in metastatic nonsmall cell lung carcinoma.	2000 Dec 15	11135224
[A 42-year-old patient with the hemolytic-uremic syndrome under gemcitabine therapy for an adenocarcinoma of the liver. The hemolytic-uremic syndrome and gemcitabine].	2000 Jul	10965557
Excellent response to gemcitabine in a massively pre-treated woman with extensive cutaneous involvement after recurrence of breast cancer.	2001	11291839
Achievement of complete remission in refractory Hodgkin's disease with prolonged infusion of gemcitabine.	2001	11291828
Malignant pleural mesothelioma.	2001	11224994
Lung cancer: therapeutic options for stage IV and recurrent NSCLC.	2001	11224988
Options in advanced non-small cell lung cancer: a review and report on a phase II study of vinorelbine plus gemcitabine.	2001	11182000
Activity of gemcitabine and continuous infusion fluorouracil in advanced pancreatic cancer.	2001	11150907
Topotecan and gemcitabine in platinum/paclitaxel-resistant ovarian cancer.	2001	11150903
Neoadjuvant, adjuvant, and palliative treatment of pancreatic cancer.	2001 Apr	11276380
2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine: a novel anticancer nucleoside analog that causes both DNA strand breaks and G(2) arrest.	2001 Apr	11259616
Phase II trial of two-weekly gemcitabine in patients with advanced biliary tract cancer.	2001 Feb	11300321
Challenging the platinum combinations: docetaxel (Taxotere) combined with gemcitabine or vinorelbine in non-small cell lung cancer.	2001 Feb	11284620
[Palliative therapy of pancreatic adenocarcinoma].	2001 Feb	11253511
Biweekly gemcitabine, doxorubicin, and paclitaxel as first-line treatment in metastatic breast cancer. Final results from a phase II trial.	2001 Feb	11252890
The gemcitabine/epirubicin/paclitaxel trials in advanced breast cancer.	2001 Feb	11252889
Gemcitabine, paclitaxel, and trastuzumab in metastatic breast cancer.	2001 Feb	11252888
Gemcitabine and Pemetrexed disodium in treating breast cancer.	2001 Feb	11252887
Gemcitabine as single-agent therapy in the management of advanced breast cancer.	2001 Feb	11252882
The role of apoptosis in 2',2'-difluoro-2'-deoxycytidine (gemcitabine)-mediated radiosensitization.	2001 Feb	11234886
The clinical implications of gemcitabine radiosensitization.	2001 Feb	11234872
S-Phase arrest by nucleoside analogues and abrogation of survival without cell cycle progression by 7-hydroxystaurosporine.	2001 Feb 1	11221834
End-joining deficiency and radiosensitization induced by gemcitabine.	2001 Feb 15	11245469
Gemcitabine and cisplatin for advanced, metastatic bladder cancer.	2001 Feb 15	11181690
Phase II trial of paclitaxel plus gemcitabine in patients with locally advanced or metastatic non-small-cell lung cancer.	2001 Feb 15	11181671
Gemcitabine for malignant mesothelioma: A phase II trial by the Cancer and Leukemia Group B.	2001 Feb-Mar	11165412
Activity and toxicity of gemcitabine and gemcitabine + vinorelbine in advanced non-small-cell lung cancer elderly patients: Phase II data from the Multicenter Italian Lung Cancer in the Elderly Study (MILES) randomized trial.	2001 Feb-Mar	11165408
Gemcitabine-associated posterior reversible encephalopathy syndrome: MR imaging and MR spectroscopy findings.	2001 Jan	11295355
Phase I trial of gemcitabine in patients with advanced pancreatic cancer.	2001 Jan	11256843
Second-line chemotherapy for non-small-cell lung cancer with monthly docetaxel and weekly gemcitabine: a phase II trial.	2001 Jan	11249055
Treatment of pancreatic cancer with a combination of docetaxel, gemcitabine and granulocyte colony-stimulating factor: a phase II study of the Greek Cooperative Group for Pancreatic Cancer.	2001 Jan	11249034
Irinotecan in combined-modality therapy for locally advanced non-small-cell lung cancer.	2001 Jan	11221019
Anticancer drug-induced kidney disorders.	2001 Jan	11219485
[Refractory non-small-cell lung cancer responding to combination chemotherapy with docetaxel, gemcitabine and cisplatin].	2001 Jan	11201378
Preclinical in vivo antitumor efficacy of nedaplatin with gemcitabine against human lung cancer.	2001 Jan	11173544
Fatal pulmonary veno-occlusive disease possibly related to gemcitabine.	2001 Jan	11162870
Combined use of gemcitabine and radiation in mice.	2001 Jan-Feb	11299753
Optimizing chemoradiation in locally advanced non-small-cell lung cancer.	2001 Mar	11301848
Irinotecan/gemcitabine combination chemotherapy in pancreatic cancer.	2001 Mar	11301841
Gemcitabine and vinorelbine as first-line chemotherapy for advanced non-small cell lung cancer: a phase II trial.	2001 Mar	11290433
Latent hematopoietic stem cell toxicity associated with protracted drug administration.	2001 Mar	11274755
[A case of primary malignant hemangiopericytoma of the lung with marked response to combination chemotherapy with cisplatin, ifosfamide and gemcitabine].	2001 Mar	11265407
Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas: treatment variables and survival duration.	2001 Mar	11258776
Optimizing chemoradiation therapy approaches to unresectable stage III non--small cell lung cancer.	2001 Mar	11224708
Phase I study of stealth liposomal doxorubicin in combination with gemcitabine in the treatment of patients with metastatic breast cancer.	2001 Mar 15	11251001
Steroids affect collateral sensitivity to gemcitabine of multidrug-resistant human lung cancer cells.	2001 Mar 23	11282108
Cotton-wool spots associated with pancreatic carcinoma.	2001 Mar 26	11309222
Human cytosolic 5'-nucleotidase I: characterization and role in nucleoside analog resistance.	2001 Mar 30	11133996
Akt, MAPK (Erk1/2), and p38 act in concert to promote apoptosis in response to ErbB receptor family inhibition.	2001 May 4	11278435

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%

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

INFUGEM

Brand Name

English

4-AMINO-1-((2R,4R,5R)-3,3-DIFLUORO-4-HYDROXY-5-(HYDROXYMETHYL)OXOLAN-2-YL)PYRIMIDIN-2-ONE HYDROCHLORIDE

Systematic Name

English

GEMCITABINE HYDROCHLORIDE [USP MONOGRAPH]

Common Name

English

GEMCITABINE HYDROCHLORIDE [USP-RS]

Common Name

English

GEMCITABINE HYDROCHLORIDE [MART.]

Common Name

English

GEMCITABINE HYDROCHLORIDE [JAN]

Common Name

English

LY-188011 HYDROCHLORIDE

Code

English

GEMZAR

Brand Name

English

CYTIDINE, 2'-DEOXY-2',2'-DIFLUORO-, MONOHYDROCHLORIDE

Common Name

English

2'-DEOXY-2',2'-DIFLUOROCYTIDINE MONOHYDROCHLORIDE (.BETA.-ISOMER)

Common Name

English

GEMCITABINE HYDROCHLORIDE [USAN]

Common Name

English

LY188011 HYDROCHLORIDE

Code

English

GEMCITABINE HYDROCHLORIDE [ORANGE BOOK]

Common Name

English

GEMCITABINE HCL

Common Name

English

GEMCITABINE (AS HYDROCHLORIDE)

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C1557