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Record Information
StatusDetected and Quantified
Creation Date2005-11-16 15:48:42 UTC
Update Date2020-06-15 17:04:52 UTC
Secondary Accession Numbers
  • HMDB0006206
  • HMDB0062757
  • HMDB01562
  • HMDB06206
  • HMDB62757
Metabolite Identification
Common NameFolinic acid
DescriptionFolinic acid, also known as (6S)-leucovorin or levoleucovorin, 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. Folinic acid is a moderately basic compound (based on its pKa). In humans, folinic acid is involved in folate malabsorption, hereditary. Folinic acid is a potentially toxic compound. As Folinic acid 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). Following oral administration, Folinic acid is rapidly absorbed. Folylpolyglutamates are active and participate in biochemical pathways that require reduced folate. Should not be administered intrathecally as this may produce severe adverse effects or even death when administered. In vivo, Folinic acid is converted to 5-methyltetrahydrofolic acid (5-methyl-THF), the primary circulating form of active reduced folate. As Folinic acid and Folinic acid 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. Hepatic and intestinal mucosal, the main metabolite being the active 5-methyltetrahydrofolate. Folinic acid and 5-methyl-THF are polyglutamated intracellularly by the enzyme folylpolyglutamate synthetase.
(6S)-5-Formyl-5,6,7,8-tetrahydrofolic acidChEBI
(6S)-Folinic acidChEBI
Citrovorum factorChEBI
L-Folinic acidChEBI
Levofolinic acidChEBI
N-[4-({[(6S)-2-amino-5-formyl-4-oxo-1,4,5,6,7,8-hexahydropteridin-6-yl]methyl}amino)benzoyl]-L-glutamic acidChEBI
5 FormyltetrahydropteroylglutamateHMDB
Calcium folinateHMDB
Folinic acid-SFHMDB
Leucovorin, (S)-isomerHMDB
Leucovorin, monosodium saltHMDB
Leucovorin, (R)-isomerHMDB
Leucovorin, calciumHMDB
Leucovorin, calcium (1:1) salt, (DL)-isomerHMDB
Leucovorin, calcium (1:1) salt, (S)-isomerHMDB
Monosodium salt leucovorinHMDB
Levo leucovorinHMDB
6 S LeucovorinHMDB
Acid, folinicHMDB
Factor, citrovorumHMDB
Folinic acid SFHMDB
Leucovorin, calcium (1:1) salt, pentahydrateHMDB
Leucovorin, monopotassium salt, (S)-isomerHMDB
5 FormyltetrahydrofolateHMDB
6S LeucovorinHMDB
Calcium leucovorinHMDB
Folinate, calciumHMDB
Leucovorin, (D)-isomerHMDB
Leucovorin, (DL)-isomerHMDB
Leucovorin, calcium (1:1) saltHMDB
Leucovorin, monosodium salt, (S)-isomerHMDB
S LeucovorinHMDB
5-Formyl-(6S)-tetrahydrofolic acidHMDB
5-Formyl-5,6,7,8-tetrahydrofolic acidHMDB
5-Formyltetrahydrofolic acidHMDB
5-Formyltetrahydropteroylglutamic acidHMDB
N5-Formyl-5,6,7,8-tetrahydrofolic acidHMDB
N5-Formyltetrahydrofolic acidHMDB
(6S)-5-Formyltetrahydrofolic acidHMDB
Folinic acidMeSH
Chemical FormulaC20H23N7O7
Average Molecular Weight473.4393
Monoisotopic Molecular Weight473.165896125
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
Traditional Name(2S)-2-{[4-({[(6S)-2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl]methyl}amino)phenyl]formamido}pentanedioic acid
CAS Registry Number68538-85-2
InChI Identifier
Chemical Taxonomy
Description 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
  • Tetrahydrofolic acid
  • Glutamic acid or derivatives
  • N-acyl-alpha amino acid or derivatives
  • N-acyl-alpha-amino acid
  • Hippuric acid
  • Hippuric acid or derivatives
  • Alpha-amino acid or derivatives
  • Aminobenzamide
  • Aminobenzoic acid or derivatives
  • Benzamide
  • Benzoic acid or derivatives
  • Benzoyl
  • Aniline or substituted anilines
  • Phenylalkylamine
  • Aminopyrimidine
  • Secondary aliphatic/aromatic amine
  • Pyrimidone
  • Dicarboxylic acid or derivatives
  • Benzenoid
  • Pyrimidine
  • Monocyclic benzene moiety
  • Heteroaromatic compound
  • Vinylogous amide
  • Tertiary carboxylic acid amide
  • Secondary carboxylic acid amide
  • Amino acid or derivatives
  • Amino acid
  • Carboxamide group
  • Secondary amine
  • Carboxylic acid
  • Carboxylic acid derivative
  • Azacycle
  • Organooxygen compound
  • Carbonyl group
  • Organic nitrogen compound
  • Hydrocarbon derivative
  • Amine
  • Organic oxide
  • Organopnictogen compound
  • Organic oxygen compound
  • Primary amine
  • Organonitrogen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors


Biological location:


Naturally occurring process:

Physical Properties
Experimental Properties
Melting PointNot AvailableNot Available
Boiling PointNot AvailableNot Available
Water SolubilityNot AvailableNot Available
LogPNot AvailableNot Available
Predicted Properties
Water Solubility0.3 g/LALOGPS
pKa (Strongest Acidic)3.47ChemAxon
pKa (Strongest Basic)2.81ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count12ChemAxon
Hydrogen Donor Count7ChemAxon
Polar Surface Area215.55 ŲChemAxon
Rotatable Bond Count9ChemAxon
Refractivity126.46 m³·mol⁻¹ChemAxon
Polarizability46.34 ųChemAxon
Number of Rings3ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Spectrum TypeDescriptionSplash KeyView
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0adi-0031900000-15cbae867ecd4a003ef0Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0a6r-0393400000-73f11f6c59198eafb45fSpectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0pb9-0591000000-ea5c6303d77ffa4af0cbSpectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-00di-0000900000-a3ae54a4d9b2cae45b72Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-00bc-1243900000-4ea7b3b1902e6a1204e5Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0007-7973000000-df3edd5bd8661611dd06Spectrum
Biological Properties
Cellular Locations
  • Extracellular
Biospecimen Locations
  • Blood
Tissue Locations
  • Bladder
  • Fibroblasts
  • Pancreas
  • Testis
Normal Concentrations
BloodDetected and Quantified0.0025 +/- 0.0036 uMAdult (>18 years old)BothNormal details
Abnormal Concentrations
Not Available
Associated Disorders and Diseases
Disease ReferencesNone
Associated OMIM IDsNone
DrugBank IDDB11596
Phenol Explorer Compound IDNot Available
FooDB IDFDB022689
KNApSAcK IDNot Available
Chemspider ID131714
KEGG Compound IDC03479
BioCyc IDNot Available
BiGG IDNot Available
Wikipedia LinkFolinic acid
METLIN IDNot Available
PubChem Compound149436
PDB IDNot Available
ChEBI ID63606
Food Biomarker OntologyNot Available
Synthesis ReferenceZakrzewski, Sigmund F.; Sansone, Annette M. Preparation of folinic acid (N5-formyltetrahydro folic acid). Methods Enzymol. (1971), 18(Pt. B), 731-3.
Material Safety Data Sheet (MSDS)Not Available
General References
  1. Micke O, Bruns F, Schafer U, Kurowski R, Horst E, Willich N: CA 19-9 in the therapy monitoring and follow-up of locally advanced cancer of the exocrine pancreas treated with radiochemotherapy. Anticancer Res. 2003 Mar-Apr;23(2A):835-40. [PubMed:12820309 ]
  2. Garbis SD, Melse-Boonstra A, West CE, van Breemen RB: Determination of folates in human plasma using hydrophilic interaction chromatography-tandem mass spectrometry. Anal Chem. 2001 Nov 15;73(22):5358-64. [PubMed:11816560 ]
  3. Pfeiffer CM, Fazili Z, McCoy L, Zhang M, Gunter EW: Determination of folate vitamers in human serum by stable-isotope-dilution tandem mass spectrometry and comparison with radioassay and microbiologic assay. Clin Chem. 2004 Feb;50(2):423-32. Epub 2003 Dec 11. [PubMed:14670827 ]
  4. Karakayali FY, Bayar S, Hazinedaroglu S, Sahin F, Karayalcin K: Does folinic acid have a choleretic effect on humans? Turk J Gastroenterol. 2003 Jun;14(2):102-5. [PubMed:14614635 ]
  5. Perry TL, Applegarth DA, Evans ME, Hansen S, Jellum E: Metabolic studies of a family with massive formiminoglutamic aciduria. Pediatr Res. 1975 Mar;9(3):117-22. [PubMed:235753 ]
  6. Pineda M, Ormazabal A, Lopez-Gallardo E, Nascimento A, Solano A, Herrero MD, Vilaseca MA, Briones P, Ibanez L, Montoya J, Artuch R: Cerebral folate deficiency and leukoencephalopathy caused by a mitochondrial DNA deletion. Ann Neurol. 2006 Feb;59(2):394-8. [PubMed:16365882 ]
  7. Birmingham BK, Greene DS: Analysis of folinic acid in human serum using high-performance liquid chromatography with amperometric detection. J Pharm Sci. 1983 Nov;72(11):1306-9. [PubMed:6606033 ]
  8. Sengelov L, von der Maase H, Lundbeck F, Barlebo H, Colstrup H, Engelholm SA, Krarup T, Madsen EL, Meyhoff HH, Mommsen S, Nielsen OS, Pedersen D, Steven K, Sorensen B: Neoadjuvant chemotherapy with cisplatin and methotrexate in patients with muscle-invasive bladder tumours. Acta Oncol. 2002;41(5):447-56. [PubMed:12442921 ]
  9. Bunni MA, Priest DG: Human red blood cell-mediated metabolism of leucovorin [(R,S)5-formyltetrahydrofolate]. Arch Biochem Biophys. 1991 May 1;286(2):633-7. [PubMed:1897982 ]
  10. Ramaekers VT, Hausler M, Opladen T, Heimann G, Blau N: Psychomotor retardation, spastic paraplegia, cerebellar ataxia and dyskinesia associated with low 5-methyltetrahydrofolate in cerebrospinal fluid: a novel neurometabolic condition responding to folinic acid substitution. Neuropediatrics. 2002 Dec;33(6):301-8. [PubMed:12571785 ]
  11. Zhu WY, Alliegro MA, Melera PW: The rate of folate receptor alpha (FR alpha) synthesis in folate depleted CHL cells is regulated by a translational mechanism sensitive to media folate levels, while stable overexpression of its mRNA is mediated by gene amplification and an increase in transcript half-life. J Cell Biochem. 2001 Mar 26;81(2):205-19. [PubMed:11241661 ]
  12. Jansman FG, Coenen JL, De Graaf JC, Tobi H, Sleijfer DT, Brouwers JR: Relationship between pharmacokinetics of 5-FU in plasma and in saliva, and toxicity of 5-fluorouracil/folinic acid. Anticancer Res. 2002 Nov-Dec;22(6B):3449-55. [PubMed:12552938 ]
  13. Vimercati A, Greco P, D'Apolito A, Angelici MC, Possenti A, Carbonara S, Selvaggi L: [Risk assessment of vertical transmission of Toxoplasma infections]. Acta Biomed Ateneo Parmense. 2000;71 Suppl 1:537-40. [PubMed:11424802 ]
  14. Joulia JM, Pinguet F, Ychou M, Duffour J, Astre C, Bressolle F: Plasma and salivary pharmacokinetics of 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer receiving 5-FU bolus plus continuous infusion with high-dose folinic acid. Eur J Cancer. 1999 Feb;35(2):296-301. [PubMed:10448274 ]
  15. Polyzos A, Kouraklis G, Giannopoulos A, Bramis J, Delladetsima JK, Sfikakis PP: Irinotecan as salvage chemotherapy for advanced small bowel adenocarcinoma: a series of three patients. J Chemother. 2003 Oct;15(5):503-6. [PubMed:14598944 ]
  16. Straw JA, Szapary D, Wynn WT: Pharmacokinetics of the diastereoisomers of leucovorin after intravenous and oral administration to normal subjects. Cancer Res. 1984 Jul;44(7):3114-9. [PubMed:6609768 ]
  17. Micke O, Hesselmann S, Bruns F, Horst E, Devries A, Schuller P, Willich N, Schafer U: Results and follow-up of locally advanced cancer of the exocrine pancreas treated with radiochemotherapy. Anticancer Res. 2005 May-Jun;25(3A):1523-30. [PubMed:16033054 ]
  18. Bentivoglio G, Melica F, Cristoforoni P: Folinic acid in the treatment of human male infertility. Fertil Steril. 1993 Oct;60(4):698-701. [PubMed:8405528 ]
  19. Kajiyama Y, Tsurumaru M, Udagawa H, Tsutsumi K, Kinoshita Y, Akiyama H: Relief of jaundice by 5-fluorouracil and folinic acid in patients with recurrent gastric cancer. Surg Oncol. 1996 Aug;5(4):177-81. [PubMed:9067566 ]
  20. Jardine LF, Ingram LC, Bleyer WA: Intrathecal leucovorin after intrathecal methotrexate overdose. J Pediatr Hematol Oncol. 1996 Aug;18(3):302-4. [PubMed:8689347 ]


General function:
Involved in catalytic activity
Specific function:
Folate-dependent enzyme, that displays both transferase and deaminase activity. Serves to channel one-carbon units from formiminoglutamate to the folate pool. Binds and promotes bundling of vimentin filaments originating from the Golgi (By similarity).
Gene Name:
Uniprot ID:
Molecular weight:
Folinic acid + L-Glutamic acid → Tetrahydrofolic acid + N-Formyl-L-glutamic aciddetails
Folinic acid + L-Glutamic acid → Tetrahydrofolic acid + N-Formyl-L-glutamic aciddetails
General function:
Involved in aminomethyltransferase activity
Specific function:
The glycine cleavage system catalyzes the degradation of glycine.
Gene Name:
Uniprot ID:
Molecular weight:
Folinic acid → 5,10-Methenyltetrahydrofolic acid + Waterdetails
General function:
Involved in ATP binding
Specific function:
Contributes to tetrahydrofolate metabolism. Helps regulate carbon flow through the folate-dependent one-carbon metabolic network that supplies carbon for the biosynthesis of purines, thymidine and amino acids.
Gene Name:
Uniprot ID:
Molecular weight:
Adenosine triphosphate + Folinic acid → ADP + Phosphate + 5,10-Methenyltetrahydrofolic aciddetails
Adenosine triphosphate + Folinic acid + Hydrogen Ion → ADP + Phosphate + 5,10-Methenyltetrahydrofolic aciddetails
General function:
Involved in thymidylate synthase activity
Specific function:
Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.
Gene Name:
Uniprot ID:
Molecular weight:
  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:12453856 ]
  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:15025795 ]
  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:16251201 ]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]


General function:
Involved in ATP binding
Specific function:
Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter
Gene Name:
Uniprot ID:
Molecular weight:
  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:15618649 ]
  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:12874005 ]
General function:
Involved in ATP binding
Specific function:
May act as an inducible transporter in the biliary and intestinal excretion of organic anions. Acts as an alternative route for the export of bile acids and glucuronides from cholestatic hepatocytes
Gene Name:
Uniprot ID:
Molecular weight:
  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:11585759 ]
  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:12874005 ]
General function:
Involved in ATP binding
Specific function:
May be an organic anion pump relevant to cellular detoxification
Gene Name:
Uniprot ID:
Molecular weight:
  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:12036927 ]