LEVOLEUCOVORIN

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C20H23N7O7
Molecular Weight	473.4393
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

NC1=NC(=O)C2=C(NC[C@H](CNC3=CC=C(C=C3)C(=O)N[C@@H](CCC(O)=O)C(O)=O)N2C=O)N1

InChI

InChIKey=VVIAGPKUTFNRDU-STQMWFEESA-N

InChI=1S/C20H23N7O7/c21-20-25-16-15(18(32)26-20)27(9-28)12(8-23-16)7-22-11-3-1-10(2-4-11)17(31)24-13(19(33)34)5-6-14(29)30/h1-4,9,12-13,22H,5-8H2,(H,24,31)(H,29,30)(H,33,34)(H4,21,23,25,26,32)/t12-,13-/m0/s1

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020140s002lbl.pdf

Levoleucovorin is the pharmacologically active isomer of leucovorin or 5-formyl tetrahydrofolic acid, a folate analog . Levoleucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “onecarbon” moieties. Administration of levoleucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. Levoleucovorin can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy such as 5-fluorouracil. 5-fluorouracil is metabolized to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), which binds to and inhibits thymidylate synthase (an enzyme important in DNA repair and replication). Levoleucovorin is readily converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of FdUMP to thymidylate synthase and thereby enhances the inhibition of this enzyme. Fusilev® (levoleucovorin) is approved by FDA for i) rescue after high-dose methotrexate therapy in osteosarcoma, ii) diminishing the toxicity and counteracting the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists and iii) in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer.

Approval Year

Conditions

Condition	Modality	Targets	Highest Phase	Product
Methotrexate toxicity 4 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020140s002lbl.pdf	Secondary		Approved 8429	FUSILEV Approved Use Fusilev is a folate analog indicated for: Rescue after high-dose methotrexate therapy in osteosarcoma. Diminishing the toxicity and counteracting the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists. Use in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer. Launch Date 2008
Metastatic colorectal cancer 14 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020140s002lbl.pdf	Palliative		Approved 8429	FUSILEV Approved Use Fusilev is a folate analog indicated for: Rescue after high-dose methotrexate therapy in osteosarcoma. Diminishing the toxicity and counteracting the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists. Use in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer. Launch Date 2008

C_max

Value	Dose	Analyte	Population
10895 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020140s002lbl.pdf	200 mg/m² single, intravenous dose: 200 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered:	LEVOLEUCOVORIN unknown	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
340 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8405015/	12.5 mg single, oral dose: 12.5 mg route of administration: Oral experiment type: SINGLE co-administered:	LEVOMEFOLIC ACID serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
275 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020140s002lbl.pdf	15 mg single, intravenous dose: 15 mg route of administration: Intravenous experiment type: SINGLE co-administered:	LEVOMEFOLIC ACID serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
4930 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020140s002lbl.pdf	200 mg/m² single, intravenous dose: 200 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered:	LEVOMEFOLIC ACID unknown	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
30719 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020140s002lbl.pdf	200 mg/m² single, intravenous dose: 200 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered:	LEVOLEUCOVORIN unknown	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
1563 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8405015/	12.5 mg single, oral dose: 12.5 mg route of administration: Oral experiment type: SINGLE co-administered:	LEVOMEFOLIC ACID serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
52105 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020140s002lbl.pdf	200 mg/m² single, intravenous dose: 200 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered:	LEVOMEFOLIC ACID unknown	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
6.8 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020140s002lbl.pdf	15 mg single, intravenous dose: 15 mg route of administration: Intravenous experiment type: SINGLE co-administered:		LEVOMEFOLIC ACID serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
250 mg/m2 1 times / 2 weeks multiple, intravenous Higher than recommended Dose: 250 mg/m2, 1 times / 2 weeks Route: intravenous Route: multiple Dose: 250 mg/m2, 1 times / 2 weeks Co-administed with:: irinotecan, i.v(200 mg/m2) 5-fluorouracil, i.v(850 mg/m2) Sources: https://pubmed.ncbi.nlm.nih.gov/16197624 Page: p.207	unhealthy, 39 n = 254 Health Status: unhealthy Condition: Colorectal cancer Age Group: 39 Sex: M+F Population Size: 254 Sources: https://pubmed.ncbi.nlm.nih.gov/16197624 Page: p.207	Other AEs: Neutropenia... Other AEs: Neutropenia (grade 4, 15%) Sources: https://pubmed.ncbi.nlm.nih.gov/16197624 Page: p.207
300 mg/m2 1 times / day multiple, intravenous Highest studied dose Dose: 300 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 300 mg/m2, 1 times / day Co-administed with:: etoposide, i.v(100 mg/m2/day; days 2-4) 5-fluorouracil, i.v(500 mg/m2/day; days 1-5) Sources: https://pubmed.ncbi.nlm.nih.gov/9703859 Page: p.320	unhealthy, 66 n = 36 Health Status: unhealthy Condition: Gastric cancer Age Group: 66 Sex: M+F Population Size: 36 Sources: https://pubmed.ncbi.nlm.nih.gov/9703859 Page: p.320	Other AEs: Leucopenia... Other AEs: Leucopenia (grade 4) Sources: https://pubmed.ncbi.nlm.nih.gov/9703859 Page: p.320

AEs

AE	Significance	Dose	Population
Neutropenia	grade 4, 15%	250 mg/m2 1 times / 2 weeks multiple, intravenous Higher than recommended Dose: 250 mg/m2, 1 times / 2 weeks Route: intravenous Route: multiple Dose: 250 mg/m2, 1 times / 2 weeks Co-administed with:: irinotecan, i.v(200 mg/m2) 5-fluorouracil, i.v(850 mg/m2) Sources: https://pubmed.ncbi.nlm.nih.gov/16197624 Page: p.207	unhealthy, 39 n = 254 Health Status: unhealthy Condition: Colorectal cancer Age Group: 39 Sex: M+F Population Size: 254 Sources: https://pubmed.ncbi.nlm.nih.gov/16197624 Page: p.207
Leucopenia	grade 4	300 mg/m2 1 times / day multiple, intravenous Highest studied dose Dose: 300 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 300 mg/m2, 1 times / day Co-administed with:: etoposide, i.v(100 mg/m2/day; days 2-4) 5-fluorouracil, i.v(500 mg/m2/day; days 1-5) Sources: https://pubmed.ncbi.nlm.nih.gov/9703859 Page: p.320	unhealthy, 66 n = 36 Health Status: unhealthy Condition: Gastric cancer Age Group: 66 Sex: M+F Population Size: 36 Sources: https://pubmed.ncbi.nlm.nih.gov/9703859 Page: p.320

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P001LWX
1PlusChem LLC	1P003AHN
1PlusChem LLC	1P00E96Q
1PlusChem LLC	1P00IN2C
A2B Chem	AA74257
A2B Chem	AB52763
A2B Chem	AG64290
ABI Chem	AC1L3Z4B
AK Scientific	8293AA
AK Scientific	F327
AK Scientific	X6774
AbovChem LLC	HY-13664
AbovChem LLC	HY-13667
AbovChem LLC	HY-17556
AbovChem LLC	HY-B0080
Acros Organics	23031
Alfa Chemistry	H60181
Alinda	IVK/0069367
Ambeed	A161998
Angene	AGN-PC-0Q8DUL
ApexBio Technology	B7886
Apollo Scientific	BIC0607
AstaTech	41091
AstaTech	45502
AstaTech	C75821
BLD Pharm	BD01264222	http://www.bldpharm.com/products/68538-85-2.html
BOC Sciences	21314
BOC Sciences	42476-21-1
BOC Sciences	80433-71-2
Bide Pharmatech	BD119699
Bosche Scientific	C2170
Bosche Scientific	F1267
Bosche Scientific	L2408
Capot Chemical	3247
Cayman Chemical	20383
Changzhou Highassay Chemical Co., Ltd	my_sub1198
Chem Scene	CS-1363
Chem Scene	CS-1777
Chem Scene	CS-2466
ChemShuttle	141369
ChemShuttle	141592
ChemShuttle	159932
ChemTik	CTK5C8151
Compound Cloud	149436
Compound Cloud	15150
Compound Cloud	23048788
Compound Cloud	23684576
Compound Cloud	9892583
Enamine	EN300-6729871
Enamine	EN300-6735051
Fluorochem	205871
Fluorochem	36567
Hairui	HR129597
Hangzhou APIChem Technology	AC-13429
Hangzhou APIChem Technology	AC-24017
Hangzhou APIChem Technology	AC-7456
Hangzhou APIChem Technology	AC-7461
Hangzhou Yuhao Chemical Technology	LL0016
Hangzhou Yuhao Chemical Technology	LL2378
Hangzhou Yuhao Chemical Technology	LT1249
KeyOrganics	AS-13746
KeyOrganics	AS-19313
Lab Network	12
Lab Network	LN01753631
Lab Seeker	SC-12117
MedChem Express	HY-13664
MedChem Express	HY-13667
MedChem Express	HY-B0080
MolPort	MolPort-006-113-241
MolPort	MolPort-016-633-192
MolPort	MolPort-038-428-214
MolPort	MolPort-042-644-432
MolPort	MolPort-046-417-335
Molnova	M15258
MuseChem	I013887
MuseChem	R032753
Norris Pharm	NSZB-A219745
Norris Pharm	NSZB-A223024
NovoSeek	149436
PI Chemicals	PI-12413
PI Chemicals	PI-35185
Pharmeks	PHAR011363
Ryan Scientific	Clemastine_fumarate
Selleck Chemicals	S5136
Smolecule	S532956	http://www.smolecule.com/products/s532956
StruChem	SC-12117
THE BioTek	bt-273416	https://www.thebiotek.com/product/inhibitors/bt-273416
Tetrahedron	TS72289
Toronto Research Chemicals	F680320
Toronto Research Chemicals	L330400
Vitas-M Laboratory	STL504714
W&J PharmaChem	50A332047
ZINC	ZINC000009212427	http://zinc15.docking.org/substances/ZINC000009212427
eMolecules	195184701
eMolecules	300050154
eMolecules	300082952
eMolecules	300083208
eMolecules	31588910
eNovation Chemicals	D378122
eNovation Chemicals	D491443
eNovation Chemicals	K35779
mcule	MCULE-1227580954
mcule	MCULE-1499784734
mcule	MCULE-7934610627
mcule	MCULE-8534376696
mcule	MCULE-9660913532

PubMed

Title	Date	PubMed
Intrathecal leucovorin after intrathecal methotrexate overdose.	1996 Aug	8689347
Lack of catalytic activity of a murine mRNA cytoplasmic serine hydroxymethyltransferase splice variant: evidence against alternative splicing as a regulatory mechanism.	2001 Apr 24	11305908
Re-evaluation of the metabolism of oral doses of racemic carbon-6 isomers of formyltetrahydrofolate in human subjects.	2001 Jun	11430769
Syntheses of labeled vitamers of folic acid to be used as internal standards in stable isotope dilution assays.	2002 Aug 14	12166957
10-formyltetrahydrofolate dehydrogenase, one of the major folate enzymes, is down-regulated in tumor tissues and possesses suppressor effects on cancer cells.	2002 May	12065246
Role of the C-terminus and the long cytoplasmic loop in reduced folate carrier expression and function.	2002 May 1	12007575
Specific and sensitive quantification of folate vitamers in foods by stable isotope dilution assays using high-performance liquid chromatography-tandem mass spectrometry.	2003 May	12698226
Selective preservation of pemetrexed pharmacological activity in HeLa cells lacking the reduced folate carrier: association with the presence of a secondary transport pathway.	2004 May 1	15126375
Characterization of a folate transporter in HeLa cells with a low pH optimum and high affinity for pemetrexed distinct from the reduced folate carrier.	2004 Sep 15	15448015
The relationship between folate transport activity at low pH and reduced folate carrier function in human Huh7 hepatoma cells.	2005 Aug 30	16109384
5-Formyltetrahydrofolate is an inhibitory but well tolerated metabolite in Arabidopsis leaves.	2005 Jul 15	15888445
Structural and functional characterization of a 5,10-methenyltetrahydrofolate synthetase from Mycoplasma pneumoniae (GI: 13508087).	2005 Nov 1	16104022
Higher plant plastids and cyanobacteria have folate carriers related to those of trypanosomatids.	2005 Nov 18	16162503
Inhibition of 5,10-methenyltetrahydrofolate synthetase.	2007 Feb 15	17250800
Commentary: a case for minimizing folate supplementation in clinical regimens with pemetrexed based on the marked sensitivity of the drug to folate availability.	2007 Jul	17673612
pH stability of individual folates during critical sample preparation steps in prevision of the analysis of plant folates.	2007 Nov-Dec	17624887
High-dose folate and dietary purines promote scavenging of peroxynitrite-derived radicals--clinical potential in inflammatory disorders.	2009 Nov	19409716
The effect of folinic acid supplementation on homocysteine concentrations in newborns.	2010 Nov	20823897
Properties of the Arg376 residue of the proton-coupled folate transporter (PCFT-SLC46A1) and a glutamine mutant causing hereditary folate malabsorption.	2010 Nov	20686069
Development and analysis of an in vivo-compatible metabolic network of Mycobacterium tuberculosis.	2010 Nov 23	21092312

Sample Use Guides

In Vivo Use Guide

Fusilev Rescue After High-Dose Methotrexate Therapy: Fusilev rescue recommendations are based on a methotrexate dose of 12 grams/m2 administered by intravenous infusion over 4 hours. Fusilev rescue at a dose of 7.5 mg (approximately 5 mg/m2) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion. Fusilev Administration in Combination with 5-Fluorouracil (5-FU): The following regimens have been used historically for the treatment of colorectal cancer: 1. Fusilev is administered at 100 mg/m2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-FU at 370 mg/m2 by intravenous injection. 2. Fusilev is administered at 10 mg/m by 2 intravenous injection followed by 5-FU at 425 mg/m2 by intravenous injection.

Route of Administration: Intravenous

Name

Type

Language

LEVOLEUCOVORIN

Common Name

English

LEVOFOLINIC ACID

Common Name

English

L-FOLINIC ACID

Common Name

English

Levofolinic acid [WHO-DD]

Common Name

English

L-GLUTAMIC ACID, N-(4-((((6S)-2-AMINO-5-FORMYL-1,4,5,6,7,8-HEXAHYDRO-4-OXO-6-PTERIDINYL)METHYL)AMINO)BENZOYL)-

Common Name

English

(S)-LEUCOVORIN

Common Name

English

LFP-754

Code

English

LEVOLEUCOVORIN [VANDF]

Common Name

English

(6S)-LEUCOVORIN

Common Name

English

KHAPZORY

Brand Name

English

LEVOFOLENE

Common Name

English

LEVOLEUCOVORIN [ORANGE BOOK]

Common Name

English

Classification Tree Code System Code

LIVERTOX

554