Levoleucovorin

Identification

Summary

Levoleucovorin is a folate analog used after high dose methotrexate for osteosarcoma, to reduce the toxic effects of folate analogs, and with 5-fluorouracil in palliative treatment of advanced metastatic colorectal cancer.

Brand Names
Fusilev, Khapzory
Generic Name
Levoleucovorin
DrugBank Accession Number
DB11596
Background

Levoleucovorin is the enantiomerically active form of Folinic Acid (also known as 5-formyl tetrahydrofolic acid or leucovorin). Commercially available leucovorin is composed of a 1:1 racemic mixture of the dextrorotary and levorotary isomers, while levoleucovorin contains only the pharmacologically active levo-isomer. In vitro, the levo-isomer has been shown to be rapidly converted to the biologically available methyl-tetrahydrofolate form while the dextro form is slowly excreted by the kidneys. Despite this difference in activity, the two commercially available forms have been shown to be pharmacokinetically identical and may be used interchangeably with limited differences in efficacy or side effects (Kovoor et al, 2009).

As folate analogs, levoleucovorin and leucovorin are both used to counteract the toxic effects of folic acid antagonists, such as methotrexate, which act by inhibiting the enzyme dihydrofolate reductase (DHFR). They are indicated for use as rescue therapy following use of high-dose methotrexate in the treatment of osteosarcoma or for diminishing the toxicity associated with inadvertent overdosage of folic acid antagonists. Levoleucovorin, as the product Fusilev (FDA), has an additional indication for use in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer.

Folic acid is an essential B vitamin required by the body for the synthesis of purines, pyrimidines, and methionine before incorporation into DNA or protein. However, in order to function in this role, it must first be reduced by the enzyme dihydrofolate reductase (DHFR) into the cofactors dihydrofolate (DHF) and tetrahydrofolate (THF). This important pathway, which is required for de novo synthesis of nucleic acids and amino acids, is disrupted when high-dose methotrexate is used for cancer therapy. As methotrexate functions as a DHFR inhibitor to prevent DNA synthesis in rapidly dividing cells, it also prevents the formation of DHF and THF. This results in a deficiency of coenzymes and a resultant buildup of toxic substances that are responsible for numerous adverse side effects of methotrexate therapy. As levoleucovorin and leucovorin are analogs of tetrahydrofolate (THF), they are able to bypass DHFR reduction and act as a cellular replacement for the co-factor THF, thereby preventing these toxic side effects.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 473.4393
Monoisotopic: 473.165896125
Chemical Formula
C20H23N7O7
Synonyms
  • (6S)-5-Formyl-5,6,7,8-tetrahydrofolic acid
  • (6S)-5-formyltetrahydrofolic acid
  • (6S)-Folinic acid
  • (6S)-Leucovorin
  • (S)-Leucovorin
  • ácido levofolínico
  • Citrovorum factor
  • L-Folinic acid
  • Levofolene
  • Levofolinic acid
  • N-[4-({[(6S)-2-amino-5-formyl-4-oxo-1,4,5,6,7,8-hexahydropteridin-6-yl]methyl}amino)benzoyl]-L-glutamic acid
External IDs
  • LFP 754
  • LFP-754
  • LFP754

Pharmacology

Indication

Levoleucovorin is indicated for use as rescue therapy following high-dose methotrexate in the treatment of osteosarcoma or for diminishing the toxicity associated with inadvertent overdosage of folic acid antagonists. Levoleucovorin, as the product Fusilev (FDA, dosed at one-half the usual dose of racemic d,l-leucovorin), has an additional indication for use in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer (although they should not be mixed in the same infusion as a precipitate may form).

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination for symptomatic treatment ofAdvanced colorectal cancerRegimen in combination with: Fluorouracil (DB00544)••••••••••••
Treatment ofFolic acid antagonist overdose••••••••••••
Used in combination for symptomatic treatment ofMetastatic colorectal cancerRegimen in combination with: Fluorouracil (DB00544)••••••••••••
Associated Therapies
Contraindications & Blackbox Warnings
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Pharmacodynamics

Levoleucovorin is actively and passively transported across cell membranes. In vivo, levoleucovorin is converted to 5-methyltetrahydrofolic acid (5-methyl-THF), the primary circulating form of active reduced folate. Levoleucovorin and 5-methyl-THF are polyglutamated intracellularly by the enzyme folylpolyglutamate synthetase. Folylpolyglutamates are active and participate in biochemical pathways that require reduced folate.

Mechanism of action

Folic acid is an essential B vitamin required by the body for the synthesis of purines, pyrimidines, and methionine before incorporation into DNA or protein. However, in order to function in this role, it must first be reduced by the enzyme dihydrofolate reductase (DHFR) into the cofactors dihydrofolate (DHF) and tetrahydrofolate (THF). This important pathway, which is required for de novo synthesis of nucleic acids and amino acids, is disrupted when high-dose methotrexate is used for cancer therapy. As methotrexate functions as a DHFR inhibitor to prevent DNA synthesis in rapidly dividing cells, it also prevents the formation of DHF and THF. This results in a deficiency of coenzymes and a resultant buildup of toxic substances that are responsible for numerous adverse side effects of methotrexate therapy. As levoleucovorin and leucovorin are analogs of tetrahydrofolate (THF), they are able to bypass DHFR reduction and act as a cellular replacement for the co-factor THF, thereby preventing these toxic side effects.

TargetActionsOrganism
USerine hydroxymethyltransferaseNot AvailableShigella flexneri
Absorption

After rapid intravenous administration, serum total tetrahydrofolate (total-THF) concentrations reached a mean peak of 1722 ng/mL. Serum (6S)-5-methyl-5,6,7,8-tetrahydrofolate concentrations reached a mean peak of 275 ng/mL and the mean time to peak was 0.9 hours.

Volume of distribution

Data can't be found.

Protein binding

Does not bind human serum albumin.

Metabolism

Extensively converted to tetrahydrofolic derivatives.

Hover over products below to view reaction partners

Route of elimination

Urinary.

Half-life

The mean terminal half-life for total-THF and (6S)-5-methyl-5,6,7,8-tetrahydrofolate was 5.1 and 6.8 hours, respectively.

Clearance

Data can't be found.

Adverse Effects
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Toxicity

ِAcute intravenous LD50 values in adult mice and rats were 575 mg/kg (1725 mg/m²) and 378 mg/kg ( 2268 mg/m²), respectively.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
CapecitabineThe risk or severity of adverse effects can be increased when Levoleucovorin is combined with Capecitabine.
CarbamazepineThe serum concentration of Levoleucovorin can be decreased when it is combined with Carbamazepine.
ColestipolThe serum concentration of Levoleucovorin can be decreased when it is combined with Colestipol.
CycloguanilThe therapeutic efficacy of Cycloguanil can be decreased when used in combination with Levoleucovorin.
DapsoneThe therapeutic efficacy of Dapsone can be decreased when used in combination with Levoleucovorin.
Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Levoleucovorin calcium778XL6VBS880433-71-2KVUAALJSMIVURS-QNTKWALQSA-L
Levoleucovorin calcium pentahydrateWA16A5Y52X419573-16-3NPPBLUASYYNAIG-BWDMFOMUSA-L
Levoleucovorin disodium5TXQ76K65T1141892-29-6FSDMNNPYPVJNAT-NJHZPMQHSA-L
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
FusilevInjection, solution10 mg/1mLIntravenousSpectrum Pharmaceuticals, Inc.2011-09-152019-02-28US flag
FusilevInjection, powder, lyophilized, for solution50 mg/5mLIntravenousAcrotech Biopharma Inc2008-08-15Not applicableUS flag
FusilevInjection, powder, lyophilized, for solution50 mg/5mLIntravenousSpectrum Pharmaceuticals, Inc.2008-08-152019-02-28US flag
FusilevInjection, solution10 mg/1mLIntravenousAcrotech Biopharma Llc2011-09-15Not applicableUS flag
FusilevInjection, powder, lyophilized, for solution50 mg/5mLIntravenousCangene Bio Pharma2008-08-152010-02-24US flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
LevoleucovorinInjection, solution10 mg/1mLIntravenousMeitheal Pharmaceuticals Inc.2019-08-16Not applicableUS flag
LevoleucovorinInjection10 mg/1mLIntravenousGland Pharma Limited2018-09-20Not applicableUS flag
LevoleucovorinInjection, powder, lyophilized, for solution50 mg/1IntravenousAmneal Pharmaceuticals LLC2017-02-13Not applicableUS flag
LevoleucovorinInjection10 mg/1mLIntravenousFosun Pharma USA Inc.2019-06-25Not applicableUS flag
LevoleucovorinInjection, solution175 mg/17.5mLIntravenousDr.Reddy's Laboratories Inc2018-09-26Not applicableUS flag
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Biopar delta-FORTELevoleucovorin (2.5 mg/1) + Cobalamin (50 ug/1) + Cobamamide (50 ug/1) + Dihydrofolic Acid (1 mg/1) + Gastric intrinsic factor (50 mg/1) + Levomefolate magnesium (7 mg/1)CapsuleOralJaymac Pharma2023-06-01Not applicableUS flag

Categories

ATC Codes
V03AF10 — Sodium levofolinateV03AF04 — Calcium levofolinate
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as tetrahydrofolic acids. These are heterocyclic compounds based on the 5,6,7,8-tetrahydropteroic acid skeleton conjugated with at least one L-glutamic acid unit.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pteridines and derivatives
Sub Class
Pterins and derivatives
Direct Parent
Tetrahydrofolic acids
Alternative Parents
Glutamic acid and derivatives / Hippuric acids / N-acyl-alpha amino acids / Aminobenzamides / Aniline and substituted anilines / Benzoyl derivatives / Phenylalkylamines / Secondary alkylarylamines / Aminopyrimidines and derivatives / Pyrimidones
show 13 more
Substituents
Alpha-amino acid or derivatives / Amine / Amino acid / Amino acid or derivatives / Aminobenzamide / Aminobenzoic acid or derivatives / Aminopyrimidine / Aniline or substituted anilines / Aromatic heteropolycyclic compound / Azacycle
show 33 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
5-formyltetrahydrofolic acid (CHEBI:63606)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
990S25980Y
CAS number
68538-85-2
InChI Key
VVIAGPKUTFNRDU-STQMWFEESA-N
InChI
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
IUPAC Name
(2S)-2-{[4-({[(6S)-2-amino-5-formyl-4-oxo-1,4,5,6,7,8-hexahydropteridin-6-yl]methyl}amino)phenyl]formamido}pentanedioic acid
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

References

General References
  1. Kovoor PA, Karim SM, Marshall JL: Is levoleucovorin an alternative to racemic leucovorin? A literature review. Clin Colorectal Cancer. 2009 Oct;8(4):200-6. doi: 10.3816/CCC.2009.n.034. [Article]
  2. Allegra CJ, Chabner BA, Drake JC, Lutz R, Rodbard D, Jolivet J: Enhanced inhibition of thymidylate synthase by methotrexate polyglutamates. J Biol Chem. 1985 Aug 15;260(17):9720-6. [Article]
  3. Stover PJ, Field MS: Trafficking of intracellular folates. Adv Nutr. 2011 Jul;2(4):325-31. doi: 10.3945/an.111.000596. Epub 2011 Jun 28. [Article]
  4. Chuang VT, Suno M: Levoleucovorin as replacement for leucovorin in cancer treatment. Ann Pharmacother. 2012 Oct;46(10):1349-57. doi: 10.1345/aph.1Q677. Epub 2012 Oct 2. [Article]
  5. Zittoun J: Pharmacokinetics and in vitro studies of l-leucovorin. Comparison with the d and d,l-leucovorin. Ann Oncol. 1993;4 Suppl 2:1-5. [Article]
  6. Schilsky RL, Ratain MJ: Clinical pharmacokinetics of high-dose leucovorin calcium after intravenous and oral administration. J Natl Cancer Inst. 1990 Sep 5;82(17):1411-5. [Article]
  7. product info [Link]
  8. product info [Link]
KEGG Drug
D04715
PubChem Compound
149436
PubChem Substance
347828002
ChemSpider
131714
BindingDB
286
RxNav
877015
ChEBI
63606
ChEMBL
CHEMBL1908841
ZINC
ZINC000009212427
PharmGKB
PA450198
PDBe Ligand
FFO
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Folinic_acid
PDB Entries
1dfo / 1eqb / 1jol / 1jom / 1pj7 / 1wop / 2vmy / 3sd3 / 3suh / 3uwl
show 10 more
FDA label
Download (5.52 MB)

Clinical Trials

Clinical Trials

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral
Injection, powder, for solutionIntramuscular; Intravenous; Parenteral
Injection, powder, for solutionIntramuscular; Intravenous; Parenteral25 MG
Injection, powder, for solutionIntravenous10 MG/ML
Injection, powder, for solutionIntravenous100 MG
Injection, powder, for solutionIntravenous175 MG
TabletOral
Injection, powder, lyophilized, for solutionIntravenous50 mg/5mL
Injection, powder, lyophilized, for solutionIntravenous175 mg/3.5mL
Injection, powder, lyophilized, for solutionIntravenous300 mg/6mL
Granule, for solutionOral2.5 MG
Granule, for solutionOral5 mg
Injection, powder, for solutionIntramuscular1.5 MG/3ML
Injection, powder, for solutionIntravenous25 MG
Injection, powder, lyophilized, for solutionIntravenous1.5 mg
Injection, solutionIntramuscular1.5 MG/1ML
Powder, for solutionIntravenous100 MG
Powder, for solutionIntravenous175 MG
Injection, powder, for solutionParenteral7.5 MG/1ML
SolutionOral7.5 MG/10ML
TabletOral15 MG
TabletOral4 MG
TabletOral7.5 MG
InjectionIntravenous10 mg/1mL
Injection, powder, lyophilized, for solutionIntravenous10 mg/1mL
Injection, powder, lyophilized, for solutionIntravenous50 mg/1
Injection, solutionIntravenous175 mg/17.5mL
Injection, solutionIntravenous250 mg/25mL
Injection, solutionIntravenous10 mg/1mL
Injection, solutionIntravenous10 mg/1
Injection, powder, for solutionIntramuscular; Intravenous; Parenteral100 MG
Injection, powder, for solutionIntramuscular; Intravenous; Parenteral175 MG
Injection, solutionIntravenous50 MG/ML
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US6500829No2002-12-312022-03-07US flag
US11541012No2019-03-252039-03-25US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.3 mg/mLALOGPS
logP-1.1ALOGPS
logP-3.8Chemaxon
logS-3.2ALOGPS
pKa (Strongest Acidic)3.21Chemaxon
pKa (Strongest Basic)4.66Chemaxon
Physiological Charge-2Chemaxon
Hydrogen Acceptor Count12Chemaxon
Hydrogen Donor Count7Chemaxon
Polar Surface Area215.55 Å2Chemaxon
Rotatable Bond Count9Chemaxon
Refractivity126.46 m3·mol-1Chemaxon
Polarizability44.58 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-004i-0019100000-a096d918af5b91166cbf
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-0000900000-ed115a407d32d9a21741
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-057j-1589300000-11633c2aeb57ee72e2d1
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0f89-0902600000-5398a3bd75e206b3ccd7
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-00l2-0900000000-c4cef20d0365aebdf55b
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0uxu-5974500000-cc4f6b1e9afd065bc75b
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-231.2484854
predicted
DarkChem Lite v0.1.0
[M-H]-199.82112
predicted
DeepCCS 1.0 (2019)
[M+H]+230.8904854
predicted
DarkChem Lite v0.1.0
[M+H]+202.21669
predicted
DeepCCS 1.0 (2019)
[M+Na]+231.8744854
predicted
DarkChem Lite v0.1.0
[M+Na]+208.1292
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Shigella flexneri
Pharmacological action
Unknown
Curator comments
Levoleucovorin, a pharmacologically active levo-isomer of racemic leucovirin, has been shown to be an inhibitor of this enzyme in vitro. However, clinically, it is not used for this purpose.
General Function
Pyridoxal phosphate binding
Specific Function
Catalyzes the reversible interconversion of serine and glycine with tetrahydrofolate (THF) serving as the one-carbon carrier. This reaction serves as the major source of one-carbon groups required ...
Gene Name
glyA
Uniprot ID
P0A827
Uniprot Name
Serine hydroxymethyltransferase
Molecular Weight
45316.33 Da
References
  1. Schirch V, Szebenyi DM: Serine hydroxymethyltransferase revisited. Curr Opin Chem Biol. 2005 Oct;9(5):482-7. doi: 10.1016/j.cbpa.2005.08.017. [Article]
  2. Chang WN, Tsai JN, Chen BH, Huang HS, Fu TF: Serine hydroxymethyltransferase isoforms are differentially inhibited by leucovorin: characterization and comparison of recombinant zebrafish serine hydroxymethyltransferases. Drug Metab Dispos. 2007 Nov;35(11):2127-37. doi: 10.1124/dmd.107.016840. Epub 2007 Jul 30. [Article]
  3. Stover P, Schirch V: 5-Formyltetrahydrofolate polyglutamates are slow tight binding inhibitors of serine hydroxymethyltransferase. J Biol Chem. 1991 Jan 25;266(3):1543-50. [Article]
  4. Pai VR, Rajaram V, Bisht S, Bhavani BS, Rao NA, Murthy MR, Savithri HS: Structural and functional studies of Bacillus stearothermophilus serine hydroxymethyltransferase: the role of Asn(341), Tyr(60) and Phe(351) in tetrahydrofolate binding. Biochem J. 2009 Mar 15;418(3):635-42. doi: 10.1042/BJ20081739. [Article]
  5. Paiardini A, Fiascarelli A, Rinaldo S, Daidone F, Giardina G, Koes DR, Parroni A, Montini G, Marani M, Paone A, McDermott LA, Contestabile R, Cutruzzola F: Screening and in vitro testing of antifolate inhibitors of human cytosolic serine hydroxymethyltransferase. ChemMedChem. 2015 Mar;10(3):490-7. doi: 10.1002/cmdc.201500028. Epub 2015 Feb 10. [Article]

Drug created at May 19, 2016 19:51 / Updated at March 18, 2024 16:24