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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
Structure for Levoleucovorin (DB11596)
- 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).
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used in combination for symptomatic treatment of Advanced colorectal cancer Regimen in combination with: Fluorouracil (DB00544) •••••••••••• Treatment of Folic acid antagonist overdose •••••••••••• Used in combination for symptomatic treatment of Metastatic colorectal cancer Regimen in combination with: Fluorouracil (DB00544) •••••••••••• - Associated Therapies
- Contraindications & Blackbox Warnings
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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.
Target Actions Organism USerine hydroxymethyltransferase Not Available Shigella 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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ِ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.
Drug Interaction Integrate drug-drug
interactions in your softwareCapecitabine The risk or severity of adverse effects can be increased when Levoleucovorin is combined with Capecitabine. Carbamazepine The serum concentration of Levoleucovorin can be decreased when it is combined with Carbamazepine. Colestipol The serum concentration of Levoleucovorin can be decreased when it is combined with Colestipol. Cycloguanil The therapeutic efficacy of Cycloguanil can be decreased when used in combination with Levoleucovorin. Dapsone The therapeutic efficacy of Dapsone can be decreased when used in combination with Levoleucovorin. - Food Interactions
- No interactions found.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Levoleucovorin calcium 778XL6VBS8 80433-71-2 KVUAALJSMIVURS-QNTKWALQSA-L Levoleucovorin calcium pentahydrate WA16A5Y52X 419573-16-3 NPPBLUASYYNAIG-BWDMFOMUSA-L Levoleucovorin disodium 5TXQ76K65T 1141892-29-6 FSDMNNPYPVJNAT-NJHZPMQHSA-L - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Fusilev Injection, powder, lyophilized, for solution 50 mg/5mL Intravenous Spectrum Pharmaceuticals, Inc. 2008-08-15 2019-02-28 US 
Fusilev Injection, solution 10 mg/1mL Intravenous Acrotech Biopharma Inc 2011-09-15 Not applicable US Fusilev Injection, powder, lyophilized, for solution 50 mg/5mL Intravenous Cangene Bio Pharma 2008-08-15 2010-02-24 US Fusilev Injection, solution 10 mg/1mL Intravenous Acrotech Biopharma Inc 2011-09-15 Not applicable US Fusilev Injection, solution 10 mg/1mL Intravenous Spectrum Pharmaceuticals, Inc. 2011-09-15 2019-02-28 US - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Levoleucovorin Injection, solution 175 mg/17.5mL Intravenous Dr. Reddy's Laboratories Limited 2018-09-26 Not applicable US Levoleucovorin Injection, solution 10 mg/1mL Intravenous Ingenus Pharmaceuticals, LLC 2018-05-08 Not applicable US Levoleucovorin Injection, solution 175 mg/17.5mL Intravenous Sandoz S.P.A. 2015-04-23 2023-04-30 US Levoleucovorin Injection, solution 250 mg/25mL Intravenous Northstar RxLLC 2018-09-26 Not applicable US Levoleucovorin Injection, solution 10 mg/1mL Intravenous Ingenus Pharmaceuticals, LLC 2018-05-08 Not applicable US - Unapproved/Other Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Biopar delta-FORTE Levoleucovorin (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) Capsule Oral Jaymac Pharmaceuticals Llc 2024-06-01 Not applicable US
Categories
- ATC Codes
- V03AF10 — Sodium levofolinate
- V03AF — Detoxifying agents for antineoplastic treatment
- V03A — ALL OTHER THERAPEUTIC PRODUCTS
- V03 — ALL OTHER THERAPEUTIC PRODUCTS
- V — VARIOUS
- Drug Categories
- Antidotes
- Coenzymes
- Compounds used in a research, industrial, or household setting
- Detoxifying Agents for Antineoplastic Treatment
- Enzymes and Coenzymes
- Folate Analog
- Folic Acid Analogues
- Folic Acid and Derivatives
- Formyltetrahydrofolates
- Heterocyclic Compounds, Fused-Ring
- Micronutrients
- Protective Agents
- Pteridines
- Pterins
- Tetrahydrofolates
- Vitamin B Complex
- Vitamins
- 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
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- product info [Link]
- product info [Link]
- External Links
- KEGG Drug
- D04715
- PubChem Compound
- 149436
- PubChem Substance
- 347828002
- ChemSpider
- 131714
- BindingDB
- 286
- 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 14 more
- FDA label
- Download (5.52 MB)
Clinical Trials
- Clinical Trials
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Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral Injection, powder, for solution Intramuscular; Intravenous; Parenteral Injection, powder, for solution Intramuscular; Intravenous; Parenteral 25 MG Injection, powder, for solution Intravenous 10 MG/ML Injection, powder, for solution Intravenous 100 MG Injection, powder, for solution Intravenous 175 MG Tablet Oral Injection, powder, lyophilized, for solution Intravenous 50 mg/5mL Injection, powder, lyophilized, for solution Intravenous 175 mg/3.5mL Injection, powder, lyophilized, for solution Intravenous 300 mg/6mL Granule, for solution Oral 2.5 MG Granule, for solution Oral 5 mg Injection, powder, for solution Intramuscular 1.5 MG/3ML Injection, powder, for solution Intravenous 25 MG Injection, powder, lyophilized, for solution Intravenous 1.5 mg Injection, solution Intramuscular 1.5 MG/1ML Powder, for solution Intravenous 100 MG Powder, for solution Intravenous 175 MG Injection, powder, for solution Parenteral 7.5 MG/1ML Solution Oral 7.5 MG/10ML Tablet Oral 15 MG Tablet Oral 4 MG Tablet Oral 7.5 MG Injection Intravenous 10 mg/1mL Injection, powder, lyophilized, for solution Intravenous 10 mg/1mL Injection, powder, lyophilized, for solution Intravenous 50 mg/1 Injection, solution Intravenous 175 mg/17.5mL Injection, solution Intravenous 250 mg/25mL Injection, solution Intravenous 10 mg/1 Injection, solution Intravenous 10 mg/1mL Injection, powder, for solution Intramuscular; Intravenous; Parenteral 100 MG Injection, powder, for solution Intramuscular; Intravenous; Parenteral 175 MG Injection, solution Intravenous 50 MG/ML - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US6500829 No 2002-12-31 2022-03-07 US US11541012 No 2019-03-25 2039-03-25 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.3 mg/mL ALOGPS logP -1.1 ALOGPS logP -3.8 Chemaxon logS -3.2 ALOGPS pKa (Strongest Acidic) 3.21 Chemaxon pKa (Strongest Basic) 4.66 Chemaxon Physiological Charge -2 Chemaxon Hydrogen Acceptor Count 12 Chemaxon Hydrogen Donor Count 7 Chemaxon Polar Surface Area 215.55 Å2 Chemaxon Rotatable Bond Count 9 Chemaxon Refractivity 126.46 m3·mol-1 Chemaxon Polarizability 44.58 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-004i-0019100000-a096d918af5b91166cbf Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-004i-0000900000-ed115a407d32d9a21741 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-057j-1589300000-11633c2aeb57ee72e2d1 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0f89-0902600000-5398a3bd75e206b3ccd7 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-00l2-0900000000-c4cef20d0365aebdf55b Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0uxu-5974500000-cc4f6b1e9afd065bc75b Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 231.2484854 predictedDarkChem Lite v0.1.0 [M-H]- 199.82112 predictedDeepCCS 1.0 (2019) [M+H]+ 230.8904854 predictedDarkChem Lite v0.1.0 [M+H]+ 202.21669 predictedDeepCCS 1.0 (2019) [M+Na]+ 231.8744854 predictedDarkChem Lite v0.1.0 [M+Na]+ 208.1292 predictedDeepCCS 1.0 (2019)
Targets
- 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
- 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 for the biosynthesis of purines, thymidylate, methionine, and other important biomolecules. Also exhibits THF-independent aldolase activity toward beta-hydroxyamino acids, producing glycine and aldehydes, via a retro-aldol mechanism.
- Specific Function
- cobalt ion binding
- Gene Name
- glyA
- Uniprot ID
- P0A827
- Uniprot Name
- Serine hydroxymethyltransferase
- Molecular Weight
- 45316.33 Da
References
- 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]
- 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]
- 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]
- 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]
- 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 October 12, 2024 23:56