LEVOLEUCOVORIN CALCIUM

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C20H21N7O7.Ca
Molecular Weight	511.501
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[Ca++].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=KVUAALJSMIVURS-QNTKWALQSA-L

InChI=1S/C20H23N7O7.Ca/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);/q;+2/p-2/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
Ontogeny of hepatic enzymes involved in serine- and folate-dependent one-carbon metabolism in rabbits.	2001 May	11292595
Residues 45 and 404 in the murine reduced folate carrier may interact to alter carrier binding and mobility.	2003 Jun 27	12832086
5,10-methenyltetrahydrofolate cyclohydrolase, rat liver and chemically catalysed formation of 5-formyltetrahydrofolate.	2003 Sep 15	12793858
Lack of impact of the loss of constitutive folate receptor alpha expression, achieved by RNA Interference, on the activity of the new generation antifolate pemetrexed in HeLa cells.	2004 Dec 1	15585634
A prominent low-pH methotrexate transport activity in human solid tumors: contribution to the preservation of methotrexate pharmacologic activity in HeLa cells lacking the reduced folate carrier.	2004 Jan 15	14760095
Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphisms: relationships with 5-fluorouracil sensitivity.	2004 Jan 26	14735204
Serine hydroxymethyltransferase: role of glu75 and evidence that serine is cleaved by a retroaldol mechanism.	2004 Jun 8	15170323
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
Development of a simplified method for the determination of folates in baker's yeast by HPLC with ultraviolet and fluorescence detection.	2005 Apr 6	15796570
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
Methenyltetrahydrofolate synthetase is a high-affinity catecholamine-binding protein.	2006 Nov 15	17055997
Neural tube defects and disturbed maternal folate- and homocysteine-mediated one-carbon metabolism.	2008 Aug	18589417
Folate in wheat genotypes in the HEALTHGRAIN Diversity Screen.	2008 Nov 12	18921972
The clinical course and genetic defect in the PCFT gene in a 27-year-old woman with hereditary folate malabsorption.	2008 Sep	18718264
The proton-coupled folate transporter: impact on pemetrexed transport and on antifolates activities compared with the reduced folate carrier.	2008 Sep	18524888
Role of the glutamate 185 residue in proton translocation mediated by the proton-coupled folate transporter SLC46A1.	2009 Jul	19403800
High-dose folate and dietary purines promote scavenging of peroxynitrite-derived radicals--clinical potential in inflammatory disorders.	2009 Nov	19409716
One-carbon metabolism in plants: characterization of a plastid serine hydroxymethyltransferase.	2010 Aug 15	20518745
Cerebral folate deficiency presenting as adolescent catatonic schizophrenia: a case report.	2010 Jul	20445197
Quantification of folate in fruits and vegetables: A fluorescence-based homogeneous assay.	2010 Jul 15	20361923
The effect of folinic acid supplementation on homocysteine concentrations in newborns.	2010 Nov	20823897
Mutation of the proton-coupled folate transporter gene (PCFT-SLC46A1) in Turkish siblings with hereditary folate malabsorption.	2010 Nov	20795774
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
Production of folate by bacteria isolated from oat bran.	2010 Sep 30	20708290

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 CALCIUM

Official Name

English

CL 307,782

Code

English

CALCIUM (6S)-FOLINATE

Common Name

English

LEVOLEUCOVORIN CALCIUM [VANDF]

Common Name

English

FOLINIC ACID L-FORM CALCIUM SALT [MI]

Common Name

English

LEVOLEUCOVORIN CALCIUM [ORANGE BOOK]

Common Name

English

CL-307782

Code

English

LEVOLEUCOVORIN CALCIUM [USAN]

Common Name

English

ELVORINE

Brand Name

English

CALCIUM LEVOFOLINATE

Official Name

English

CALCIUM LEVOFOLINATE [MART.]

Common Name

English

LEVOFOLINATE CALCIUM [JAN]

Common Name

English

LEVOFOLINATE CALCIUM

Common Name

English

(-)-5-FORMYL-(6S)-TETRAHYDROFOLATE CALCIUM SALT

Common Name

English

CALCIUM N-(P-((((6S)-AMINO-5-FORMYL-1,4,5,6,7,8-HEXAHYDRO-4-OXO-6-PTERIDINYL)METHYL)AMINO)BENZOYL)-L-GLUTAMATE (1:1)

Common Name

English

Calcium levofolinate [WHO-DD]

Common Name

English

ISOVORIN

Brand Name

English

CALCIUM LEVOFOLINATE (6S,L)

Common Name

English

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

Common Name

English

calcium levofolinate [INN]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C2078