GEMCITABINE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C9H11F2N3O4
Molecular Weight	263.1981
Optical Activity	UNSPECIFIED
Defined Stereocenters	3 / 3
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

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

InChI

InChIKey=SDUQYLNIPVEERB-QPPQHZFASA-N

InChI=1S/C9H11F2N3O4/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)/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
Acute myocardial infarction following gemcitabine therapy--a case report.	1999 Dec	10609769
Severe non-haematological toxicity after treatment with gemcitabine.	1999 Nov	10541971
Haemolytic uraemic syndrome after gemcitabine treatment for pancreatic carcinoma.	1999 Oct	10528696
Gemcitabine-induced atrial fibrillation: a hitherto unreported manifestation of drug toxicity.	2000 Apr	10847470
Phase I study of paclitaxel and day 1/day 8 gemcitabine in patients with solid malignancies.	2000 Aug	10955861
Paclitaxel-induced stomal neuropathy: a unique cause of pain in a patient with ileal conduit.	2000 Dec 20	11113764
A dose-finding study of gemcitabine and vinorelbine in advanced previously treated malignancies.	2000 Jan	10690391
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
Chemotherapy of metastatic breast cancer: what to expect in 2001 and beyond.	2001	11306725
Induction chemotherapy followed by concomitant chemoradiotherapy for non-small cell lung cancer.	2001	11182002
Options in advanced non-small cell lung cancer: a review and report on a phase II study of vinorelbine plus gemcitabine.	2001	11182000
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
Gemcitabine following radiotherapy with concurrent 5-fluorouracil for nonmetastatic adenocarcinoma of the pancreas.	2001 Apr 20	11291097
Challenging the platinum combinations: docetaxel (Taxotere) combined with gemcitabine or vinorelbine in non-small cell lung cancer.	2001 Feb	11284620
Gemcitabine and paclitaxel as salvage therapy in metastatic breast cancer.	2001 Feb	11252885
Treatment of advanced breast cancer with gemcitabine and vinorelbine.	2001 Feb	11252883
Chemotherapy agents in transitional cell carcinoma: the old and the new.	2001 Feb	11246730
Effects of gemcitabine on cisplatin-induced nephrotoxicity in rats: schedule-dependent study.	2001 Feb	11243722
Syntheses and antitumor activities of potent inhibitors of ribonucleotide reductase: 3-amino-4-methylpyridine-2-carboxaldehyde-thiosemicarba-zone (3-AMP), 3-amino-pyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) and its water-soluble prodrugs.	2001 Feb	11172670
End-joining deficiency and radiosensitization induced by gemcitabine.	2001 Feb 15	11245469
P53 modulates the effect of loss of DNA mismatch repair on the sensitivity of human colon cancer cells to the cytotoxic and mutagenic effects of cisplatin.	2001 Feb 15	11245458
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
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
High-dose thiotepa and melphalan with hemopoietic progenitor support following induction therapy with epirubicin-paclitaxel-containing regimens in metastatic breast cancer (MBC).	2001 Jan	11249051
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
Docetaxel followed by gemcitabine and irinotecan in solid tumors.	2001 Jan	11221020
Irinotecan in combined-modality therapy for locally advanced non-small-cell lung cancer.	2001 Jan	11221019
Treatment of non-small-cell lung cancer in North America: the emerging role of irinotecan.	2001 Jan	11221017
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
Preirradiation gemcitabine chemotherapy for newly diagnosed glioblastoma. A phase II study.	2001 Jan 15	11180090
Optimizing chemoradiation in locally advanced non-small-cell lung cancer.	2001 Mar	11301848
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
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
Combined radiochemotherapy of locally advanced unresectable pancreatic adenocarcinoma with mitomycin C plus 24-hour continuous infusional gemcitabine.	2001 Mar 1	11172947
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

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

Official Name

English

GEMCITABINE [USAN]

Common Name

English

LY188011

Code

English

GEMCITABINE [MI]

Common Name

English

GEMCITABINE [HSDB]

Common Name

English

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

Systematic Name

English

LY-188011

Code

English

NSC-613327

Code

English

GEMCITABINE [VANDF]

Common Name

English

2'-DEOXY-2',2'-DIFLUOROCYTIDINE

Systematic Name

English

gemcitabine [INN]

Common Name

English

Gemcitabine [WHO-DD]

Common Name

English

Classification Tree Code System Code

WHO-VATC

QL01BC05