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targets (1) transporters (3)
for drugs
Identification
Name Leucovorin
Accession Number DB00650 (APRD00698)
Type small molecule
Groups approved
Description

The active metabolite of folic acid. Leucovorin is used principally as its calcium salt as an antidote to folic acid antagonists which block the conversion of folic acid to folinic acid. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Calcium folinate
  • Folinic acid
  • Folinic acid calcium salt
  • Folinic acid calcium salt USP27
  • L-leucovorin
  • Leucovorin calcium
  • Leucovorin folinic acid
Brand names
  • Calcium citrovorum factor
  • Citrovorum factor
  • Folinic acid-SF
  • Leucal
  • Wellcovorin
Brand name mixtures Not Available
Categories
  • Antianemic Agents
  • Antidote (to folic acid antagonists)
  • Antineoplastic Adjuncts
  • Vitamins/minerals
  • Vitamin B Complex
CAS number 1492-18-8
Weight Average: 473.4393
Monoisotopic: 473.165896125
Chemical Formula C20H23N7O7
InChI Key InChIKey=VVIAGPKUTFNRDU-ZGTCLIOFSA-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-/m1/s1
Plain Text
IUPAC Name
(2R)-2-[(4-{[(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(NCC(CNC3=CC=C(C=C3)C(=O)N[C@H](CCC(O)=O)C(O)=O)N2C=O)N1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Pterins
  • Keto-Acids
Substructures
  • Pterins
  • Hydroxy Compounds
  • Acetates
  • Aliphatic and Aryl Amines
  • Amino Ketones
  • Benzene and Derivatives
  • Carboxylic Acids and Derivatives
  • Pyrimidines and Derivatives
  • Heterocyclic compounds
  • Aromatic compounds
  • Keto-Acids
  • Carboxamides and Derivatives
  • Benzoyl Derivatives
  • Cyanamides
  • Benzamides
  • Anilines
Pharmacology
Indication For 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.
Pharmacodynamics Leucovorin 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 action As 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.
Absorption Following 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 distribution Not 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.
Route of elimination Not Available
Half life 6.2 hours
Clearance Not Available
Toxicity LD50>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 Not Available
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
Form Route Strength
Liquid Intravenous
Solution Intravenous
Tablet Oral
Prices
Unit description Cost Unit
Leucovorin calcium 25 mg tablet 24.73 USD tablet
Leucovorin calcium 500 mg vial 24.42 USD vial
Leucovorin calcium 200 mg vial 14.4 USD vial
Leucovorin calcium 350 mg vial 11.86 USD vial
Leucovorin Calcium 10 mg/ml 10.93 USD ml
Leucovorin calcium 15 mg tablet 10.61 USD tablet
Leucovorin calcium 10 mg tablet 7.69 USD tablet
Lederle Leucovorin Calcium 5 mg Tablet 6.85 USD tablet
Leucovorin calcium 100 mg vial 6.0 USD vial
Leucovorin calcium 50 mg vial 3.6 USD vial
Leucovorin calcium 5 mg tablet 2.05 USD tablet
Patents
Country Patent Number Approved Expires
United States 6500829 1999-12-31 2019-12-31
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
water solubility Complete PhysProp
logP -3.2 PhysProp
Predicted Properties
Property Value Source
water solubility 3.00e-01 g/l ALOGPS
logP -1.06 ALOGPS
logP -3.96 ChemAxon Molconvert
logS -3.20 ALOGPS
pKa 3.76 ChemAxon Molconvert
hydrogen acceptor count 12 ChemAxon Molconvert
hydrogen donor count 7 ChemAxon Molconvert
polar surface area 215.55 ChemAxon Molconvert
rotatable bond count 9 ChemAxon Molconvert
refractivity 126.46 ChemAxon Molconvert
polarizability 46.53 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Jardine LF, Ingram LC, Bleyer WA: Intrathecal leucovorin after intrathecal methotrexate overdose. J Pediatr Hematol Oncol. 1996 Aug;18(3):302-4. Pubmed
External Links
Resource Link
KEGG Drug D01211 Link_out
PubChem Compound 54575 Link_out
PubChem Substance 46505436 Link_out
ChemSpider 49292 Link_out
Therapeutic Targets Database DAP001244 Link_out
PharmGKB PA450198 Link_out
Drug Product Database 2182998 Link_out
RxList http://www.rxlist.com/cgi/generic/leucovorin.htm Link_out
Drugs.com http://www.drugs.com/cdi/leucovorin.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Leucovorin Link_out
ATC Codes
  • V03AF03
AHFS Codes
  • 92:00.00
PDB Entries Not Available
FDA label show (304.3 KB)
MSDS show (72.7 KB)
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Thymidylate synthase

Pharmacological action: yes
Actions: inhibitor
Organism class: human
UniProt ID: P04818 Link_out
Gene: TYMS Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Aschele C, Debernardis D, Bandelloni R, Cascinu S, Catalano V, Giordani P, Barni S, Turci D, Drudi G, Lonardi S, Gallo L, Maley F, Monfardini S: Thymidylate synthase protein expression in colorectal cancer metastases predicts for clinical outcome to leucovorin-modulated bolus or infusional 5-fluorouracil but not methotrexate-modulated bolus 5-fluorouracil. Ann Oncol. 2002 Dec;13(12):1882-92. Pubmed
  2. Zhu AX, Puchalski TA, Stanton VP Jr, Ryan DP, Clark JW, Nesbitt S, Charlat O, Kelly P, Kreconus E, Chabner BA, Supko JG: Dihydropyrimidine dehydrogenase and thymidylate synthase polymorphisms and their association with 5-fluorouracil/leucovorin chemotherapy in colorectal cancer. Clin Colorectal Cancer. 2004 Feb;3(4):225-34. Pubmed
  3. Smorenburg CH, Peters GJ, van Groeningen CJ, Noordhuis P, Smid K, van Riel AM, Dercksen W, Pinedo HM, Giaccone G: Phase II study of tailored chemotherapy for advanced colorectal cancer with either 5-fluouracil and leucovorin or oxaliplatin and irinotecan based on the expression of thymidylate synthase and dihydropyrimidine dehydrogenase. Ann Oncol. 2006 Jan;17(1):35-42. Epub 2005 Oct 26. Pubmed
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
Transporters

1. Multidrug resistance-associated protein 4

Actions: inhibitor

May be an organic anion pump relevant to cellular detoxification

UniProt ID: O15439 Link_out
Gene: ABCC4 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen ZS, Lee K, Walther S, Raftogianis RB, Kuwano M, Zeng H, Kruh GD: Analysis of methotrexate and folate transport by multidrug resistance protein 4 (ABCC4): MRP4 is a component of the methotrexate efflux system. Cancer Res. 2002 Jun 1;62(11):3144-50. Pubmed

2. Canalicular multispecific organic anion transporter 1

Actions: substrate, inhibitor

Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter

UniProt ID: Q92887 Link_out
Gene: ABCC2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Horikawa M, Kato Y, Tyson CA, Sugiyama Y: The potential for an interaction between MRP2 (ABCC2) and various therapeutic agents: probenecid as a candidate inhibitor of the biliary excretion of irinotecan metabolites. Drug Metab Pharmacokinet. 2002;17(1):23-33. Pubmed
  2. Chen ZS, Robey RW, Belinsky MG, Shchaveleva I, Ren XQ, Sugimoto Y, Ross DD, Bates SE, Kruh GD: Transport of methotrexate, methotrexate polyglutamates, and 17beta-estradiol 17-(beta-D-glucuronide) by ABCG2: effects of acquired mutations at R482 on methotrexate transport. Cancer Res. 2003 Jul 15;63(14):4048-54. Pubmed

3. Canalicular multispecific organic anion transporter 2

Actions: substrate

May act as an inducible transporter in the biliary and intestinal excretion of organic anions

UniProt ID: O15438 Link_out
Gene: ABCC3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zeng H, Chen ZS, Belinsky MG, Rea PA, Kruh GD: Transport of methotrexate (MTX) and folates by multidrug resistance protein (MRP) 3 and MRP1: effect of polyglutamylation on MTX transport. Cancer Res. 2001 Oct 1;61(19):7225-32. Pubmed
  2. Chen ZS, Robey RW, Belinsky MG, Shchaveleva I, Ren XQ, Sugimoto Y, Ross DD, Bates SE, Kruh GD: Transport of methotrexate, methotrexate polyglutamates, and 17beta-estradiol 17-(beta-D-glucuronide) by ABCG2: effects of acquired mutations at R482 on methotrexate transport. Cancer Res. 2003 Jul 15;63(14):4048-54. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on November 10, 2010 13:41

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.