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Identification
NameLeucovorin
Accession NumberDB00650  (APRD00698)
TypeSmall Molecule
GroupsApproved
Description

Folinic Acid (also known as 5-formyl tetrahydrofolic acid or leucovorin) is the 5-formyl derivative of tetrahydrofolic acid, a necessary co-factor in the body. 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, leucovorin and levoleucovorin 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. Injectable forms are also indicated for use in the treatment of megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible and for use in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced 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 associated with 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.

Structure
Thumb
Synonyms
(5-formyl-5,6,7,8-tetrahydropteroyl)glutamate
10-Formyl-7,8-dihydrofolic acid
5-Formyl-5,6,7,8-tetrahydrofolic acid
5-Formyl-5,6,7,8-tetrahydropteroyl-L-glutamic acid
5-Formyltetrahydrofolate
5-formyltetrahydrofolic acid
Acide folinique
folinate
Folinic acid
L(-)-5-Formyl-5,6,7,8-tetrahydrofolic acid
Leucovorinum
N-(5-formyl-5,6,7,8-tetrahydropteroyl)-L-glutamic acid
N5-Formyl-5,6,7,8-tetrahydrofolic acid
N5-Formyltetrahydrofolic acid
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Lederle Leucovorintablet5 mgoralPfizer Canada Inc1996-10-25Not applicableCanada
Lederle Leucovorin - Liq Im IV 10mg/mlliquid10 mgintramuscular; intravenousWyeth Ayerst Canada Inc.1997-02-042001-10-29Canada
Lederle Leucovorin 350mg/vialpowder for solution350 mgintramuscular; intravenousLederle Cyanamid Canada Inc.1991-12-311999-04-12Canada
Lederle Leucovorin 50mg/vialpowder for solution50 mgintramuscular; intravenousLederle Cyanamid Canada Inc.1991-12-311997-08-14Canada
Lederle Leucovorin Liq 10mg/mlliquid10 mgintramuscular; intravenousLederle Cyanamid Canada Inc.1991-12-311999-04-12Canada
Lederle Leucovorin-pws Im IV 350mg/vialpowder for solution350 mgintramuscular; intravenousWyeth Ayerst Canada Inc.1997-02-042002-05-17Canada
Lederle Leucovorin-pws Im IV 50mg/vialpowder for solution50 mgintramuscular; intravenousWyeth Ayerst Canada Inc.1997-02-042001-06-05Canada
Leucovorin Calcium Inj 10mg/mlliquid10 mgintramuscular; intravenousDavid Bull Laboratories (Pty) Ltd.1992-12-311997-08-14Canada
Leucovorin Calcium Injectionsolution10 mgintramuscular; intravenousTeva Canada Limited1994-12-31Not applicableCanada
Leucovorin Calcium Injectionsolution10 mgintramuscular; intravenousSandoz Canada IncorporatedNot applicableNot applicableCanada
Leucovorin Calcium Injection USPliquid10 mgintramuscular; intravenousHospira Healthcare Corporation1997-08-07Not applicableCanada
Leucovorin Calcium Injection USPliquid10 mgintravenousHospira Healthcare Corporation1997-05-09Not applicableCanada
Leucovorin Calcium Tab 5mgtablet5 mgoralLederle Cyanamid Canada Inc.1980-12-311997-08-14Canada
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Leucovorininjection, powder, for solution350 mg/17.5mLintramuscular; intravenousSagent Pharmaceuticals2012-09-15Not applicableUs
Leucovorininjection, powder, for solution200 mg/20mLintramuscular; intravenousSagent Pharmaceuticals2012-09-15Not applicableUs
Leucovorininjection, powder, for solution100 mg/10mLintramuscular; intravenousSagent Pharmaceuticals2012-09-15Not applicableUs
Leucovorininjection, powder, for solution50 mg/5mLintramuscular; intravenousSagent Pharmaceuticals2012-09-15Not applicableUs
Leucovorin Calciumtablet5 mg/1oralMylan Institutional Inc.1996-02-26Not applicableUs
Leucovorin Calciumtablet5 mg/1oralRoxane Laboratories, Inc.1993-02-22Not applicableUs
Leucovorin Calciumtablet5 mg/1oralREMEDYREPACK INC.2013-09-27Not applicableUs
Leucovorin Calciumtablet25 mg/1oralBarr Laboratories Inc.1990-06-30Not applicableUs
Leucovorin Calciumtablet5 mg/1oralBarr Laboratories Inc.1990-06-30Not applicableUs
Leucovorin Calciuminjection, powder, lyophilized, for solution500 mg/50mLintramuscular; intravenousFresenius Kabi USA, LLC2010-09-18Not applicableUs
Leucovorin Calciumtablet5 mg/1oralRoxane Laboratories, Inc.1993-02-22Not applicableUs
Leucovorin Calciuminjection, powder, lyophilized, for solution200 mg/20mLintramuscular; intravenousFresenius Kabi USA, LLC2010-09-18Not applicableUs
Leucovorin Calciumtablet25 mg/1oralRoxane Laboratories, Inc.1993-02-22Not applicableUs
Leucovorin Calciumtablet15 mg/1oralPhysicians Total Care, Inc.2008-07-08Not applicableUs
Leucovorin Calciumtablet15 mg/1oralRoxane Laboratories, Inc.1993-02-22Not applicableUs
Leucovorin Calciumtablet5 mg/1oralPhysicians Total Care, Inc.2002-04-15Not applicableUs
Leucovorin Calciuminjection, powder, lyophilized, for solution350 mg/17.5mLintramuscular; intravenousTeva Parenteral Medicines, Inc.1997-06-12Not applicableUs
Leucovorin Calciumtablet25 mg/1oralMylan Institutional Inc.1997-08-27Not applicableUs
Leucovorin Calciumtablet10 mg/1oralRoxane Laboratories, Inc.1993-02-22Not applicableUs
Leucovorin Calciumtablet5 mg/1oralREMEDYREPACK INC.2013-05-22Not applicableUs
Leucovorin Calciuminjection, powder, lyophilized, for solution100 mg/10mLintramuscular; intravenousTeva Parenteral Medicines, Inc.1994-02-01Not applicableUs
Levoleucovorin Calciuminjection, solution10 mg/mLintravenousMylan Institutional LLC2015-10-21Not applicableUs
Levoleucovorin Calciuminjection, solution10 mg/mLintravenousMylan Institutional LLC2015-10-21Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
UzelNot Available
WellcovorinNot Available
Brand mixtures
NameLabellerIngredients
Pyrimethamine LeucovorinSouth Coast Specialty Compounding, Inc. D/B/A Park Compounding
Salts
Name/CASStructureProperties
Leucovorin calcium
1492-18-8
Thumb
  • InChI Key: KVUAALJSMIVURS-ZEDZUCNESA-L
  • Monoisotopic Mass: 511.1128369
  • Average Mass: 511.508
DBSALT000342
Leucovorin calcium pentahydrate
6035-45-6
Thumb
  • InChI Key: NPPBLUASYYNAIG-ZIGBGYJWSA-L
  • Monoisotopic Mass: 601.1656604
  • Average Mass: 601.583
DBSALT001441
Leucovorin sodium
163254-40-8
Thumb
  • InChI Key: FSDMNNPYPVJNAT-RIWFDJIXSA-L
  • Monoisotopic Mass: 517.129785411
  • Average Mass: 517.403
DBSALT000789
Categories
UNIIQ573I9DVLP
CAS number58-05-9
WeightAverage: 473.446
Monoisotopic: 473.165896109
Chemical FormulaC20H23N7O7
InChI KeyVVIAGPKUTFNRDU-ABLWVSNPSA-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-{[(2-amino-5-formyl-4-oxo-3,4,5,6,7,8-hexahydropteridin-6-yl)methyl]amino}phenyl)formamido]pentanedioic acid
SMILES
[H]C(=O)N1C(CNC2=CC=C(C=C2)C(=O)N[C@@H](CCC(O)=O)C(O)=O)CNC2=C1C(=O)NC(N)=N2
Taxonomy
DescriptionThis 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.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassPteridines and derivatives
Sub ClassPterins and derivatives
Direct ParentTetrahydrofolic acids
Alternative Parents
Substituents
  • Tetrahydrofolic acid
  • Glutamic acid or derivatives
  • Hippuric acid or derivatives
  • Hippuric acid
  • N-acyl-alpha amino acid or derivatives
  • N-acyl-alpha-amino acid
  • Alpha-amino acid or derivatives
  • Aminobenzamide
  • Aminobenzoic acid or derivatives
  • Benzamide
  • Benzoic acid or derivatives
  • Benzoyl
  • Phenylalkylamine
  • Aniline or substituted anilines
  • Aminopyrimidine
  • Secondary aliphatic/aromatic amine
  • Pyrimidone
  • Dicarboxylic acid or derivatives
  • Monocyclic benzene moiety
  • Primary aromatic amine
  • Benzenoid
  • Pyrimidine
  • Heteroaromatic compound
  • Vinylogous amide
  • Tertiary carboxylic acid amide
  • Amino acid
  • Amino acid or derivatives
  • Secondary carboxylic acid amide
  • Carboxamide group
  • Carboxylic acid
  • Carboxylic acid derivative
  • Secondary amine
  • Azacycle
  • Organic nitrogen compound
  • Carbonyl group
  • Organonitrogen compound
  • Organooxygen compound
  • Primary amine
  • Hydrocarbon derivative
  • Organic oxide
  • Organopnictogen compound
  • Organic oxygen compound
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationFor the treatment of osteosarcoma (after high dose methotrexate therapy). Used to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists, and to treat megaloblastic anemias due to folic acid deficiency. Also used in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer.
PharmacodynamicsLeucovorin is one of several active, chemically reduced derivatives of folic acid. It is useful as an antidote to drugs which act as folic acid antagonists. Leucovorin is a mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid (THF). The biologically active compound of the mixture is the (-)-l-isomer, known as Citrovorum factor or (-)-folinic acid. Leucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “one-carbon” moieties. Administration of leucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. Leucovorin has also been used to enhance the activity of fluorouracil.
Mechanism of actionAs leucovorin is a derivative of folic acid, it can be used to increase levels of folic acid under conditions favoring folic acid inhibition (following treatment of folic acid antagonists such as methotrexate). Leucovorin enhances the activity of fluorouracil by stabilizing the bond of the active metabolite (5-FdUMP) to the enzyme thymidylate synthetase.
Related Articles
AbsorptionFollowing oral administration, leucovorin is rapidly absorbed. The apparent bioavailability of leucovorin was 97% for 25 mg, 75% for 50 mg, and 37% for 100 mg.
Volume of distributionNot Available
Protein binding~15%
Metabolism

Hepatic and intestinal mucosal, the main metabolite being the active 5-methyltetrahydrofolate. Leucovorin is readily converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of fluorodeoxyridylic acid to thymidylate synthase and thereby enhances the inhibition of this enzyme.

SubstrateEnzymesProduct
Leucovorin
Not Available
5-MethyltetrahydrofolateDetails
Route of eliminationNot Available
Half life6.2 hours
ClearanceNot Available
ToxicityLD50>8000 mg/kg (orally in rats). Excessive amounts of leucovorin may nullify the chemotherapeutic effect of folic acid antagonists.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Methylenetetrahydrofolate Reductase Deficiency (MTHFRD)DiseaseSMP00543
Methotrexate Action PathwayDrug actionSMP00432
Folate MetabolismMetabolicSMP00053
Folate malabsorption, hereditaryDiseaseSMP00724
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.5642
Blood Brain Barrier-0.7779
Caco-2 permeable-0.8957
P-glycoprotein substrateSubstrate0.7344
P-glycoprotein inhibitor INon-inhibitor0.918
P-glycoprotein inhibitor IINon-inhibitor0.984
Renal organic cation transporterNon-inhibitor0.8708
CYP450 2C9 substrateNon-substrate0.7887
CYP450 2D6 substrateNon-substrate0.814
CYP450 3A4 substrateNon-substrate0.5852
CYP450 1A2 substrateNon-inhibitor0.8748
CYP450 2C9 inhibitorNon-inhibitor0.9123
CYP450 2D6 inhibitorNon-inhibitor0.9326
CYP450 2C19 inhibitorNon-inhibitor0.8984
CYP450 3A4 inhibitorNon-inhibitor0.9475
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9292
Ames testNon AMES toxic0.7955
CarcinogenicityNon-carcinogens0.9361
BiodegradationNot ready biodegradable0.8534
Rat acute toxicity2.4254 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9283
hERG inhibition (predictor II)Non-inhibitor0.5331
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Hospira inc
  • Abic ltd
  • Abraxis pharmaceutical products
  • Bedford laboratories div ben venue laboratories inc
  • Elkins sinn div ah robins co inc
  • Pharmachemie bv
  • Pharmachemie usa inc
  • Teva parenteral medicines inc
  • App pharmaceuticals llc
  • Luitpold pharmaceuticals inc
  • Glaxosmithkline
  • Barr pharmaceuticals
  • Corepharma llc
  • Par pharmaceutical inc
  • Roxane laboratories inc
  • Sandoz inc
  • Xanodyne pharmaceutics inc
  • Spectrum pharmaceuticals inc
Packagers
Dosage forms
FormRouteStrength
Tabletoral5 mg
Powder for solutionintramuscular; intravenous350 mg
Powder for solutionintramuscular; intravenous50 mg
Liquidintramuscular; intravenous10 mg
Injection, powder, for solutionintramuscular; intravenous100 mg/10mL
Injection, powder, for solutionintramuscular; intravenous200 mg/20mL
Injection, powder, for solutionintramuscular; intravenous350 mg/17.5mL
Injection, powder, for solutionintramuscular; intravenous50 mg/5mL
Injection, powder, lyophilized, for solutionintramuscular; intravenous100 mg/10mL
Injection, powder, lyophilized, for solutionintramuscular; intravenous200 mg/20mL
Injection, powder, lyophilized, for solutionintramuscular; intravenous350 mg/17.5mL
Injection, powder, lyophilized, for solutionintramuscular; intravenous500 mg/50mL
Tabletoral10 mg/1
Tabletoral15 mg/1
Tabletoral25 mg/1
Tabletoral5 mg/1
Solutionintramuscular; intravenous10 mg
Liquidintravenous10 mg
Injection, solutionintravenous10 mg/mL
Capsuleoral
Prices
Unit descriptionCostUnit
Leucovorin calcium 25 mg tablet24.73USD tablet
Leucovorin calcium 500 mg vial24.42USD vial
Leucovorin calcium 200 mg vial14.4USD vial
Leucovorin calcium 350 mg vial11.86USD vial
Leucovorin Calcium 10 mg/ml10.93USD ml
Leucovorin calcium 15 mg tablet10.61USD tablet
Leucovorin calcium 10 mg tablet7.69USD tablet
Lederle Leucovorin Calcium 5 mg Tablet6.85USD tablet
Leucovorin calcium 100 mg vial6.0USD vial
Leucovorin calcium 50 mg vial3.6USD vial
Leucovorin calcium 5 mg tablet2.05USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point245 ºCNot Available
water solubilityCompleteNot Available
logP-3.2Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.297 mg/mLALOGPS
logP-0.46ALOGPS
logP-2.3ChemAxon
logS-3.2ALOGPS
pKa (Strongest Acidic)3.47ChemAxon
pKa (Strongest Basic)2.81ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count11ChemAxon
Hydrogen Donor Count7ChemAxon
Polar Surface Area215.55 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity126.66 m3·mol-1ChemAxon
Polarizability46.33 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

James C. Wisowaty, Roy A. Swaringen, David A. Yeowell, “Synthesis of leucovorin.” U.S. Patent US4500711, issued July, 1955.

US4500711
General References
  1. Jardine LF, Ingram LC, Bleyer WA: Intrathecal leucovorin after intrathecal methotrexate overdose. J Pediatr Hematol Oncol. 1996 Aug;18(3):302-4. [PubMed:8689347 ]
  2. 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. [PubMed:8353099 ]
  3. 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. [PubMed:23032661 ]
  4. 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. [PubMed:22332074 ]
  5. 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. [PubMed:2410416 ]
  6. 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. [PubMed:19822510 ]
External Links
ATC CodesNot Available
AHFS Codes
  • 92:00.00
PDB EntriesNot Available
FDA labelDownload (2.95 MB)
MSDSDownload (72.7 KB)
Interactions
Drug Interactions
Drug
CapecitabineThe risk or severity of adverse effects can be increased when Leucovorin is combined with Capecitabine.
FluorouracilThe risk or severity of adverse effects can be increased when Leucovorin is combined with Fluorouracil.
FosphenytoinThe serum concentration of Fosphenytoin can be decreased when it is combined with Leucovorin.
GlucarpidaseThe serum concentration of the active metabolites of Leucovorin can be reduced when Leucovorin is used in combination with Glucarpidase resulting in a loss in efficacy.
PhenobarbitalThe serum concentration of Phenobarbital can be decreased when it is combined with Leucovorin.
PhenytoinThe serum concentration of Phenytoin can be decreased when it is combined with Leucovorin.
PrimidoneThe serum concentration of Primidone can be decreased when it is combined with Leucovorin.
RaltitrexedThe therapeutic efficacy of Raltitrexed can be decreased when used in combination with Leucovorin.
TegafurThe risk or severity of adverse effects can be increased when Leucovorin is combined with Tegafur.
Food InteractionsNot Available
Comments
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Drug created on June 13, 2005 07:24 / Updated on August 17, 2016 13:48