VINORELBINE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C45H54N4O8
Molecular Weight	778.9323
Optical Activity	UNSPECIFIED
Defined Stereocenters	8 / 8
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

[H][C@@]12N3CC[C@@]14C5=CC(=C(OC)C=C5N(C)[C@@]4([H])[C@](O)([C@H](OC(C)=O)[C@]2(CC)C=CC3)C(=O)OC)[C@]6(C[C@H]7CN(CC(CC)=C7)CC8=C6NC9=C8C=CC=C9)C(=O)OC

InChI

InChIKey=GBABOYUKABKIAF-IELIFDKJSA-N

InChI=1S/C45H54N4O8/c1-8-27-19-28-22-44(40(51)55-6,36-30(25-48(23-27)24-28)29-13-10-11-14-33(29)46-36)32-20-31-34(21-35(32)54-5)47(4)38-43(31)16-18-49-17-12-15-42(9-2,37(43)49)39(57-26(3)50)45(38,53)41(52)56-7/h10-15,19-21,28,37-39,46,53H,8-9,16-18,22-25H2,1-7H3/t28-,37-,38+,39+,42+,43+,44-,45-/m0/s1

HIDE SMILES / InChI

Molecular Formula	C45H54N4O8
Molecular Weight	778.9323
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	7 / 8
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

Vinorelbine (trade name Navelbine) is a semi-synthetic vinca-alkaloid with a broad spectrum of anti-tumour activity. Vinorelbine is a mitotic spindle poison that impairs chromosomal segregation during mitosis. It blocks cells at G2/M. Microtubules (derived from polymers of tubulin) are the principal target of vinorelbine. Vinorelbine was developed by Pierre Fabre under licence from the CNRS in France. NAVELBINE (vinorelbine tartrate) as a single agent or in combination is indicated for the first line treatment of non small cell lung cancer and advanced breast cancer.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Tubulin 69	Inhibitor 8,297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Non-small cell lung cancer 206	Primary		Approved 8,429	NAVELBINE
Breast cancer 434	Primary		Approved 8,429	NAVELBINE

C_max

Value	Dose	Co-administered	Analyte	Population
761.8 ng/mL	25 mg/m² single, intravenous		VINORELBINE plasma	Homo sapiens
133.4 ng/mL	80 mg/m² single, oral		VINORELBINE plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
1042 ng × h/mL	25 mg/m² single, intravenous		VINORELBINE plasma	Homo sapiens
1299 ng × h/mL	80 mg/m² single, oral		VINORELBINE plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
37.9 h	25 mg/m² single, intravenous		VINORELBINE plasma	Homo sapiens
29.4 h	80 mg/m² single, oral		VINORELBINE plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
14.6%			VINORELBINE plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
30 mg/m2 1 times / week multiple, intravenous Recommended	unhealthy, 61 years (range: 32-79 years) n = 143	DLT: Neutropenia, Neutropenia... Other AEs: Leukopenia, Leukopenia...
100 mg/m2 1 times / week multiple, oral MTD	unhealthy, adult n = 6	DLT: Neutropenia... Other AEs: Leukopenia, Vomiting...
80 mg/m2 1 times / week multiple, oral RP2D	unhealthy, adult n = 13	DLT: Neutropenia, Neutropenia... Other AEs: Leukopenia, Vomiting...
25 mg/m2 1 times / week multiple, intravenous Recommended	unhealthy n = 212	DLT: Neutropenia... Other AEs: Anemia, Leukopenia...

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AEs

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AE	Significance	Dose	Population
Thrombocytopenia	grade 1, 4%	30 mg/m2 1 times / week multiple, intravenous Recommended	unhealthy, 61 years (range: 32-79 years) n = 143
Anemia	grade 1, 77%	30 mg/m2 1 times / week multiple, intravenous Recommended	unhealthy, 61 years (range: 32-79 years) n = 143
Neutropenia	grade 1, 80% DLT	30 mg/m2 1 times / week multiple, intravenous Recommended	unhealthy, 61 years (range: 32-79 years) n = 143
Leukopenia	grade 1, 81%	30 mg/m2 1 times / week multiple, intravenous Recommended	unhealthy, 61 years (range: 32-79 years) n = 143
Anemia	grade 3, 1%	30 mg/m2 1 times / week multiple, intravenous Recommended	unhealthy, 61 years (range: 32-79 years) n = 143

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737 inhibitor 1,587	substrate 1,037	substrate 1,217 inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C8/9 44 CYP2C19 1,478 CYP1A2 1,524 CYP2A6 707 CYP2E1 882 CYP2B6 810 P-gp 1,461 UGT 35	CYP3A 191 CYP3A5 395 CYP1A1 349 CYP1A2 1,054 CYP2A6 543 CYP2B6 664 CYP2C8 693 CYP2C19 991 CYP2E1 667 CYP2J2 56 CYP3A7 110 CYP4A11 119 P-gp 1,537 MRP2 205

Drug as perpetrator

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Target	Modality	Activity
CYP2B6 1,001	inhibitor 3,277	likely
CYP2C19 1,553	inhibitor 3,277	likely
CYP2C8/9 44	inhibitor 3,277	likely
CYP1A2 1,692	inhibitor 3,277	no [IC50 >10 uM]
CYP2A6 739	inhibitor 3,277	no [IC50 >10 uM]

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Drug as victim

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Target	Modality	Activity
CYP1A1 349	substrate 3,367	unlikely
CYP1A2 1,054	substrate 3,367	unlikely
CYP2A6 543	substrate 3,367	unlikely
CYP2B6 664	substrate 3,367	unlikely
CYP2C19 991	substrate 3,367	unlikely

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:480999	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:480999
MolPort	MolPort-006-823-869	https://www.molport.com/shop/molecule-link/MolPort-006-823-869
Selleck Chemicals	vinorelbine-navelbine	http://www.selleckchem.com/products/vinorelbine-navelbine.html
ZINC	ZINC000085536958	http://zinc15.docking.org/substances/ZINC000085536958
eMolecules	36500497	https://www.emolecules.com/cgi-bin/more?vid=36500497

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PubMed

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Title	Date	PubMed
Vinorelbine, epirubicin, and methotrexate (VEM) as primary treatment in locally advanced breast cancer.	2001	11524553
Nonanthracycline containing docetaxel-based combinations in metastatic breast cancer.	2001	11346680
Vinorelbine-based regimens as salvage treatment in patients with advanced non-small cell lung cancer: two parallel multicenter phase II trials.	2001	11340375
A phase II trial of fractionated vinorelbine/doxorubicin as first-line therapy for advanced breast cancer.	2001	11268706
Induction chemotherapy followed by concomitant chemoradiotherapy for non-small cell lung cancer.	2001	11182002

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Patents

Sample Use Guides

In Vivo Use Guide

NAVELBINE (vinorelbine tartrate) for intravenous injections is indicated for the treatment of non-small cell lung cancer. Single-Agent NAVELBINE (vinorelbine tartrate): The usual initial dose of single-agent NAVELBINE is 30 mg/m2 administered weekly. Oral NAVELBINE is indicated for the treatment of non-small cell lung cancer and advanced breast cancer. As a single agent, the recommended regimen is: First three administrations 60mg/m² of body surface area, administered once weekly. Subsequent administrations Beyond the third administration, it is recommended to increase the dose of Navelbine to 80mg/m² once weekly except in those patients for whom the neutrophil count dropped once below 500/mm3 or more than once between 500 and 1000/mm3 during the first three administrations at 60mg/m².

Route of Administration: Other

In Vitro Use Guide

IC(50) values for inhibition of HeLa cell proliferation for vinorelbine was 1.25 nM, similar to the concentrations that induced mitotic block at the metaphase/anaphase transition (3.8 nM).