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Showing drug card for Leucovorin (DB00650)

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Version 2.5
Creation Date 2005-06-13 13:24:05
Update Date 2009-04-16 16:47:51
Primary Accession Number DB00650
Secondary Accession Number
  • APRD00698
Name Leucovorin
Drug Type
  • Approved
  • Small Molecule
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]
Synonyms
  1. Calcium folinate
  2. Folinic acid
  3. Folinic acid calcium salt
  4. Folinic acid calcium salt USP27
  5. L-leucovorin
  6. Leucovorin calcium
  7. Leucovorin folinic acid
Brand Names
  1. Calcium citrovorum factor
  2. Citrovorum factor
  3. Folinic acid-SF
  4. Leucal
  5. Wellcovorin
Brand Mixtures Not Available
Chemical IUPAC Name (2R)-2-[[4-[(2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid
Chemical Formula C20H23N7O7
Chemical Structure Structure
CAS Registry Number 1492-18-8
InChI Identifier InChI=1/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/f/h23-25,29,33H,21H2
InChI Key VVIAGPKUTFNRDU-NLVBILHSDA
KEGG Drug D01211 Link Image
KEGG Compound Not Available
PubChem Compound 54575 Link Image
PubChem Substance 148853 Link Image
ChEBI ID Not Available
PharmGKB ID PA450198 Link Image
HET ID Not Available
GenBank ID Not Available
Drug ID Number [DIN] 02182998 Link Image
RxList Link http://www.rxlist.com/cgi/generic/leucovorin.htm Link Image
PDRhealth Link Not Available
Wikipedia Link http://en.wikipedia.org/wiki/Leucovorin Link Image
FDA Label
Material Safety Data Sheet (MSDS)
Synthesis Reference Not Available
Average Molecular Weight 473.4393
Monoisotopic Molecular Weight 473.1659
State Solid
Melting Point Not Available
Experimental Water Solubility Complete Source: PhysProp
Predicted Water Solubility 3.00e-01 mg/mL Calculated using ALOGPS
Experimental LogP/Hydrophobicity -3.2 Source: PhysProp
Predicted LogP -1.06 Calculated using ALOGPS
Experimental LogS Not Available
Predicted LogS -3.20 Calculated using ALOGPS
Experimental Caco2 Permeability Not Available
pKa/Isoelectric Point Not Available
Mass Spectrum Not Available
MOL File Show Link Image | Download Link Image
SDF File Show Link Image | Download Link Image
PDB File Show Link Image | Download Link Image
2D Structure
3D Structure
Experimental PDB ID Not Available
Isomeric 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
Canonical SMILES NC1=NC(=O)C2=C(NCC(CNC3=CC=C(C=C3)C(=O)NC(CCC(O)=O)C(O)=O)N2C=O)N1
Drug Category
  • Antianemic Agents
  • Antidote (to folic acid antagonists)
  • Antineoplastic Adjuncts
  • Vitamin B Complex
  • Vitamins/minerals
ATC Codes
AHFS Codes
  • 92:00.00
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.
Pharmacology 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.
Toxicity LD50>8000 mg/kg (orally in rats). Excessive amounts of leucovorin may nullify the chemotherapeutic effect of folic acid antagonists.
Protein Binding ~15%
Biotransformation 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.
Half Life 6.2 hours
Dosage Forms
Form Route
Liquid Intravenous
Solution Intravenous
Tablet Oral
Patient Information Not Available
Contraindications Show Link Image
Interactions Show Link Image
Drug Interactions Not Available
Food Interactions Not Available
Pathways Not Available
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 Link Image]
  2. Drugs.com Link Image
  3. Wikipedia Link Image
  4. RxList Link Image
Organisms Affected
  • Humans and other mammals
Targets
  1. Thymidylate synthase
Drug Target 1 [top]
Target 1 ID 359
Target 1 Name Thymidylate synthase
Target 1 Synonyms
  1. EC 2.1.1.45
  2. TS
  3. TSase
Target 1 Gene Name TYMS
Target 1 Protein Sequence >Thymidylate synthase 
PVAGSELPRRPLPPAAQERDAEPRPPHGELQYLGQIQHILRCGVRKDDRTGTGTLSVFGM
QARYSLRDEFPLLTTKRVFWKGVLEELLWFIKGSTNAKELSSKGVKIWDANGSRDFLDSL
GFSTREEGDLGPVYGFQWRHFGAEYRDMESDYSGQGVDQLQRVIDTIKTNPDDRRIIMCA
WNPRDLPLMALPPCHALCQFYVVNSELSCQLYQRSGDMGLGVPFNIASYALLTYMIAHIT
GLKPGDFIHTLGDAHIYLNHIEPLKIQLQREPRPFPKLRILRKVEKIDDFKAEDFQIEGY
NPHPTIKMEMAV
Target 1 Number of Residues 317
Target 1 Molecular Weight 35585
Target 1 Theoretical pI 7.00
Target 1 GO Classification
Function
catalytic activity
transferase activity
transferase activity, transferring one-carbon groups
methyltransferase activity
5,10-methylenetetrahydrofolate-dependent methyltransferase activity
thymidylate synthase activity
Process
physiological process
metabolism
cellular metabolism
nucleobase, nucleoside, nucleotide and nucleic acid metabolism
nucleotide metabolism
pyrimidine nucleotide metabolism
pyrimidine nucleotide biosynthesis
pyrimidine nucleoside monophosphate biosynthesis
pyrimidine deoxyribonucleoside monophosphate biosynthesis
dTMP biosynthesis
Component
Not Available
Target 1 General Function Nucleotide transport and metabolism
Target 1 Specific Function Not Available
Target 1 Pathways
Name SMPDB Link KEGG Link
One carbon pool by folate SMP00053 Link Image map00670 Link Image
Pyrimidine metabolism SMP00046 Link Image map00240 Link Image
Target 1 Reactions
  • 5,10-methylenetetrahydrofolate + dUMP = dihydrofolate + dTMP
Target 1 Pfam Domain Function
Target 1 Signals
  • None
Target 1 Transmembrane Regions
  • None
Target 1 Essentiality Non-Essential
Target 1 GenBank ID Protein 37479 Link Image
Target 1 UniProtKB/Swiss-Prot ID P04818 Link Image
Target 1 UniProtKB/Swiss-Prot Entry Name TYSY_HUMAN Link Image
Target 1 PDB ID 1JUJ Link Image
Target 1 PDB File Show
Target 1 3D Structure
Target 1 Cellular Location Not Available
Target 1 Gene Sequence >942 bp 
ATGCCTGTGGCCGGCTCGGAGCTGCCGCGCCGGCCCTTGCCCCCCGCCGCACAGGAGCGG
GACGCCGAGCCGCGTCCGCCGCACGGGGAGCTGCAGTACCTGGGGCAGATCCAACACATC
CTCCGCTGCGGCGTCAGGAAGGACGACCGCACGGGCACCGGCACCCTGTCGGTATTCGGC
ATGCAGGCGCGCTACAGCCTGAGAGATGAATTCCCTCTGCTGACAACCAAACGTGTGTTC
TGGAAGGGTGTTTTGGAGGAGTTGCTGTGGTTTATCAAGGGATCCACAAATGCTAAAGAG
CTGTCTTCCAAGGGAGTGAAAATCTGGGATGCCAATGGATCCCGAGACTTTTTGGACAGC
CTGGGATTCTCCACCAGAGAAGAAGGGGACTTGGGCCCAGTTTATGGCTTCCAGTGGAGG
CATTTTGGGGCAGAATACAGAGATATGGAATCAGATTATTCAGGACAGGGAGTTGACCAA
CTGCAAAGAGTGATTGACACCATCAAAACCAACCCTGACGACAGAAGAATCATCATGTGC
GCTTGGAATCCAAGAGATCTTCCTCTGATGGCGCTGCCTCCATGCCATGCCCTCTGCCAG
TTCTATGTGGTGAACAGTGAGCTGTCCTGCCAGCTGTACCAGAGATCGGGAGACATGGGC
CTCGGTGTGCCTTTCAACATCGCCAGCTACGCCCTGCTCACGTACATGATTGCGCACATC
ACGGGCCTGAAGCCAGGTGACTTTATACACACTTTGGGAGATGCACATATTTACCTGAAT
CACATCGAGCCACTGAAAATTCAGCTTCAGCGAGAACCCAGACCTTTCCCAAAGCTCAGG
ATTCTTCGAAAAGTTGAGAAAATTGATGACTTCAAAGCTGAAGACTTTCAGATTGAAGGG
TACAATCCGCATCCAACTATTAAAATGGAAATGGCTGTTTAG
Target 1 GenBank Gene ID
Target 1 GeneCard ID TYMS Link Image
Target 1 GenAtlas ID TYMS Link Image
Target 1 HGNC ID HGNC:12441 Link Image
Target 1 Chromosome Location 18
Target 1 Locus 18p11.32
Target 1 SNPs SNPJam Report Link Image
Target 1 General References
  1. Phan J, Steadman DJ, Koli S, Ding WC, Minor W, Dunlap RB, Berger SH, Lebioda L: Structure of human thymidylate synthase suggests advantages of chemotherapy with noncompetitive inhibitors. J Biol Chem. 2001 Apr 27;276(17):14170-7. Epub 2001 Jan 24. [PubMed Link Image]
  2. Phan J, Koli S, Minor W, Dunlap RB, Berger SH, Lebioda L: Human thymidylate synthase is in the closed conformation when complexed with dUMP and raltitrexed, an antifolate drug. Biochemistry. 2001 Feb 20;40(7):1897-902. [PubMed Link Image]
  3. Kaneda S, Nalbantoglu J, Takeishi K, Shimizu K, Gotoh O, Seno T, Ayusawa D: Structural and functional analysis of the human thymidylate synthase gene. J Biol Chem. 1990 Nov 25;265(33):20277-84. [PubMed Link Image]
  4. Takeishi K, Kaneda S, Ayusawa D, Shimizu K, Gotoh O, Seno T: Human thymidylate synthase gene: isolation of phage clones which cover a functionally active gene and structural analysis of the region upstream from the translation initiation codon. J Biochem (Tokyo). 1989 Oct;106(4):575-83. [PubMed Link Image]
  5. Davisson VJ, Sirawaraporn W, Santi DV: Expression of human thymidylate synthase in Escherichia coli. J Biol Chem. 1989 Jun 5;264(16):9145-8. [PubMed Link Image]
  6. Takeishi K, Kaneda S, Ayusawa D, Shimizu K, Gotoh O, Seno T: Nucleotide sequence of a functional cDNA for human thymidylate synthase. Nucleic Acids Res. 1985 Mar 25;13(6):2035-43. [PubMed Link Image]
  7. Shimizu K, Ayusawa D, Takeishi K, Seno T: Purification and NH2-terminal amino acid sequence of human thymidylate synthase in an overproducing transformant of mouse FM3A cells. J Biochem (Tokyo). 1985 Mar;97(3):845-50. [PubMed Link Image]
  8. Schiffer CA, Clifton IJ, Davisson VJ, Santi DV, Stroud RM: Crystal structure of human thymidylate synthase: a structural mechanism for guiding substrates into the active site. Biochemistry. 1995 Dec 19;34(50):16279-87. [PubMed Link Image]
Target 1 Drug 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 Link Image]
  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 Link Image]
  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 Link Image]

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.