U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C20H23N7O7
Molecular Weight 473.4401
Optical Activity UNSPECIFIED
Defined Stereocenters 2 / 2
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of LEVOLEUCOVORIN

SMILES

c1cc(ccc1C(=O)N[C@@]([H])(CCC(=O)O)C(=O)O)NC[C@@]2([H])CNc3c(c(nc(=N)[nH]3)O)N2C=O

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
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

Conditions

ConditionModalityTargetsHighest PhaseProduct
Secondary
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

1.20484803E12
Palliative
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

1.20484803E12
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
10895 ng/mL
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
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
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
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

AUC

ValueDoseCo-administeredAnalytePopulation
30719 ng × h/mL
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
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
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
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
6.8 h
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

Doses

DosePopulationAdverse 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: Page: p.207
unhealthy, 39
n = 254
Health Status: unhealthy
Condition: Colorectal cancer
Age Group: 39
Sex: M+F
Population Size: 254
Sources: Page: p.207
Other AEs: Neutropenia...
Other AEs:
Neutropenia (grade 4, 15%)
Sources: 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: Page: p.320
unhealthy, 66
n = 36
Health Status: unhealthy
Condition: Gastric cancer
Age Group: 66
Sex: M+F
Population Size: 36
Sources: Page: p.320
Other AEs: Leucopenia...
Other AEs:
Leucopenia (grade 4)
Sources: Page: p.320
AEs

AEs

AESignificanceDosePopulation
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: Page: p.207
unhealthy, 39
n = 254
Health Status: unhealthy
Condition: Colorectal cancer
Age Group: 39
Sex: M+F
Population Size: 254
Sources: 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: Page: p.320
unhealthy, 66
n = 36
Health Status: unhealthy
Condition: Gastric cancer
Age Group: 66
Sex: M+F
Population Size: 36
Sources: Page: p.320
Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
Intrathecal leucovorin after intrathecal methotrexate overdose.
1996 Aug
Lack of catalytic activity of a murine mRNA cytoplasmic serine hydroxymethyltransferase splice variant: evidence against alternative splicing as a regulatory mechanism.
2001 Apr 24
Ontogeny of hepatic enzymes involved in serine- and folate-dependent one-carbon metabolism in rabbits.
2001 May
Mitochondria from cultured cells derived from normal and thiamine-responsive megaloblastic anemia individuals efficiently import thiamine diphosphate.
2002 Apr 25
Decreased expression of the reduced folate carrier and folypolyglutamate synthetase is the basis for acquired resistance to the pemetrexed antifolate (LY231514) in an L1210 murine leukemia cell line.
2003 Apr 1
Uptake of 5-methyltetrahydrofolate into PC-3 human prostate cancer cells is carrier-mediated.
2003 Aug
Transport of 5-formyltetrahydrofolate into primary cultured rat astrocytes.
2003 Feb 1
Transport of 5-formyltetrahydrofolate into primary cultured cerebellar granule cells.
2003 Feb 7
Pyridoxal phosphate inhibits dynamic subunit interchange among serine hydroxymethyltransferase tetramers.
2003 Mar 21
Specific and sensitive quantification of folate vitamers in foods by stable isotope dilution assays using high-performance liquid chromatography-tandem mass spectrometry.
2003 May
Cerebral folate deficiency.
2004 Dec
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
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
Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphisms: relationships with 5-fluorouracil sensitivity.
2004 Jan 26
Cloning, expression, and purification of 5,10-methenyltetrahydrofolate synthetase from Mus musculus.
2004 Jun
Serine hydroxymethyltransferase: role of glu75 and evidence that serine is cleaved by a retroaldol mechanism.
2004 Jun 8
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
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
Development of a simplified method for the determination of folates in baker's yeast by HPLC with ultraviolet and fluorescence detection.
2005 Apr 6
The relationship between folate transport activity at low pH and reduced folate carrier function in human Huh7 hepatoma cells.
2005 Aug 30
Loss of reduced folate carrier function and folate depletion result in enhanced pemetrexed inhibition of purine synthesis.
2005 Feb 1
5-Formyltetrahydrofolate is an inhibitory but well tolerated metabolite in Arabidopsis leaves.
2005 Jul 15
Investigation of the extraction behavior of the main monoglutamate folates from spinach by liquid chromatography-electrospray ionization tandem mass spectrometry.
2005 Jun 17
Structural and functional characterization of a 5,10-methenyltetrahydrofolate synthetase from Mycoplasma pneumoniae (GI: 13508087).
2005 Nov 1
Higher plant plastids and cyanobacteria have folate carriers related to those of trypanosomatids.
2005 Nov 18
The inverse relationship between reduced folate carrier function and pemetrexed activity in a human colon cancer cell line.
2006 Feb
Mining literature for a comprehensive pathway analysis: a case study for retrieval of homocysteine related genes for genetic and epigenetic studies.
2006 Jan 23
Spontaneous neural tube defects in splotch mice supplemented with selected micronutrients.
2006 May 15
Methenyltetrahydrofolate synthetase is a high-affinity catecholamine-binding protein.
2006 Nov 15
Inhibition of 5,10-methenyltetrahydrofolate synthetase.
2007 Feb 15
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
Application of liquid chromatography-electrospray ionisation mass spectrometry for determination of dietary folates: effects of buffer nature and mobile phase composition on sensitivity and selectivity.
2007 Mar 2
pH stability of individual folates during critical sample preparation steps in prevision of the analysis of plant folates.
2007 Nov-Dec
Neural tube defects and disturbed maternal folate- and homocysteine-mediated one-carbon metabolism.
2008 Aug
Investigations of the roles of arginine 115 and lysine 120 in the active site of 5,10-methenyltetrahydrofolate synthetase from Mycoplasma pneumoniae.
2008 Aug
Folate content in sea buckthorn berries and related products (Hippophaë rhamnoides L. ssp. rhamnoides): LC-MS/MS determination of folate vitamer stability influenced by processing and storage assessed by stable isotope dilution assay.
2008 May
Effect of folate derivatives on the activity of antifolate drugs used against malaria and cancer.
2008 May
Folate in wheat genotypes in the HEALTHGRAIN Diversity Screen.
2008 Nov 12
The clinical course and genetic defect in the PCFT gene in a 27-year-old woman with hereditary folate malabsorption.
2008 Sep
The proton-coupled folate transporter: impact on pemetrexed transport and on antifolates activities compared with the reduced folate carrier.
2008 Sep
Role of the glutamate 185 residue in proton translocation mediated by the proton-coupled folate transporter SLC46A1.
2009 Jul
High-dose folate and dietary purines promote scavenging of peroxynitrite-derived radicals--clinical potential in inflammatory disorders.
2009 Nov
One-carbon metabolism in plants: characterization of a plastid serine hydroxymethyltransferase.
2010 Aug 15
Cerebral folate deficiency presenting as adolescent catatonic schizophrenia: a case report.
2010 Jul
Quantification of folate in fruits and vegetables: A fluorescence-based homogeneous assay.
2010 Jul 15
The effect of folinic acid supplementation on homocysteine concentrations in newborns.
2010 Nov
Mutation of the proton-coupled folate transporter gene (PCFT-SLC46A1) in Turkish siblings with hereditary folate malabsorption.
2010 Nov
Properties of the Arg376 residue of the proton-coupled folate transporter (PCFT-SLC46A1) and a glutamine mutant causing hereditary folate malabsorption.
2010 Nov
Development and analysis of an in vivo-compatible metabolic network of Mycobacterium tuberculosis.
2010 Nov 23
Production of folate by bacteria isolated from oat bran.
2010 Sep 30

Sample Use Guides

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
VANDF  
Common Name English
LEVOFOLINIC ACID
WHO-DD  
Common Name English
L-FOLINIC ACID
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
LEVOFOLINIC ACID [WHO-DD]
Common Name English
KHAPZORY
Brand Name English
LEVOFOLENE
Common Name English
LEVOLEUCOVORIN [ORANGE BOOK]
Common Name English
Classification Tree Code System Code
LIVERTOX 554
Created by admin on Sat Jun 26 01:18:01 UTC 2021 , Edited by admin on Sat Jun 26 01:18:01 UTC 2021
WHO-ATC V03AF10
Created by admin on Sat Jun 26 01:18:01 UTC 2021 , Edited by admin on Sat Jun 26 01:18:01 UTC 2021
WHO-ATC V03AF04
Created by admin on Sat Jun 26 01:18:01 UTC 2021 , Edited by admin on Sat Jun 26 01:18:01 UTC 2021
NCI_THESAURUS C2078
Created by admin on Sat Jun 26 01:18:01 UTC 2021 , Edited by admin on Sat Jun 26 01:18:01 UTC 2021
FDA ORPHAN DRUG 48590
Created by admin on Sat Jun 26 01:18:01 UTC 2021 , Edited by admin on Sat Jun 26 01:18:01 UTC 2021
FDA ORPHAN DRUG 48490
Created by admin on Sat Jun 26 01:18:01 UTC 2021 , Edited by admin on Sat Jun 26 01:18:01 UTC 2021
Code System Code Type Description
EPA CompTox
68538-85-2
Created by admin on Sat Jun 26 01:18:01 UTC 2021 , Edited by admin on Sat Jun 26 01:18:01 UTC 2021
PRIMARY
EVMPD
SUB34736
Created by admin on Sat Jun 26 01:18:01 UTC 2021 , Edited by admin on Sat Jun 26 01:18:01 UTC 2021
PRIMARY
NCI_THESAURUS
C1559
Created by admin on Sat Jun 26 01:18:01 UTC 2021 , Edited by admin on Sat Jun 26 01:18:01 UTC 2021
PRIMARY
CAS
68538-85-2
Created by admin on Sat Jun 26 01:18:01 UTC 2021 , Edited by admin on Sat Jun 26 01:18:01 UTC 2021
PRIMARY
RXCUI
877015
Created by admin on Sat Jun 26 01:18:01 UTC 2021 , Edited by admin on Sat Jun 26 01:18:01 UTC 2021
PRIMARY RxNorm
DRUG BANK
DB11596
Created by admin on Sat Jun 26 01:18:01 UTC 2021 , Edited by admin on Sat Jun 26 01:18:01 UTC 2021
PRIMARY
DRUG CENTRAL
4384
Created by admin on Sat Jun 26 01:18:01 UTC 2021 , Edited by admin on Sat Jun 26 01:18:01 UTC 2021
PRIMARY
FDA UNII
990S25980Y
Created by admin on Sat Jun 26 01:18:01 UTC 2021 , Edited by admin on Sat Jun 26 01:18:01 UTC 2021
PRIMARY
PUBCHEM
135398559
Created by admin on Sat Jun 26 01:18:01 UTC 2021 , Edited by admin on Sat Jun 26 01:18:01 UTC 2021
PRIMARY