Details
| Stereochemistry | ABSOLUTE |
| Molecular Formula | C20H21N7O7.Ca.5H2O |
| Molecular Weight | 601.578 |
| Optical Activity | ( - ) |
| Defined Stereocenters | 2 / 2 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
O.O.O.O.O.[Ca++].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
InChI
InChIKey=NPPBLUASYYNAIG-BWDMFOMUSA-L
InChI=1S/C20H23N7O7.Ca.5H2O/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);;5*1H2/q;+2;;;;;/p-2/t12-,13-;;;;;;/m0....../s1
| Molecular Formula | C20H23N7O7 |
| Molecular Weight | 473.4393 |
| Charge | 0 |
| Count |
|
| Stereochemistry | ABSOLUTE |
| Additional Stereochemistry | No |
| Defined Stereocenters | 2 / 2 |
| E/Z Centers | 0 |
| Optical Activity | UNSPECIFIED |
| Molecular Formula | H2O |
| Molecular Weight | 18.0153 |
| Charge | 0 |
| Count |
|
| Stereochemistry | ACHIRAL |
| Additional Stereochemistry | No |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Optical Activity | NONE |
| Molecular Formula | Ca |
| Molecular Weight | 40.078 |
| Charge | 2 |
| Count |
|
| Stereochemistry | ACHIRAL |
| Additional Stereochemistry | No |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Optical Activity | NONE |
Levoleucovorin is the pharmacologically active isomer of leucovorin or 5-formyl tetrahydrofolic acid, a folate analog . Levoleucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “onecarbon” moieties. Administration of levoleucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. Levoleucovorin can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy such as 5-fluorouracil. 5-fluorouracil is metabolized to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), which binds to and inhibits thymidylate synthase (an enzyme important in DNA repair and replication). Levoleucovorin is readily converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of FdUMP to thymidylate synthase and thereby enhances the inhibition of this enzyme. Fusilev® (levoleucovorin) is approved by FDA for i) rescue after high-dose methotrexate therapy in osteosarcoma, ii) diminishing the toxicity and counteracting the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists and iii) in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer.
Approval Year
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Secondary | FUSILEV Approved UseFusilev is a folate analog indicated for: Rescue after high-dose methotrexate therapy in osteosarcoma. Diminishing the toxicity and counteracting the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists. Use in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer. Launch Date2008 |
|||
| Palliative | FUSILEV Approved UseFusilev is a folate analog indicated for: Rescue after high-dose methotrexate therapy in osteosarcoma. Diminishing the toxicity and counteracting the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists. Use in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer. Launch Date2008 |
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
340 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8405015/ |
12.5 mg single, oral dose: 12.5 mg route of administration: Oral experiment type: SINGLE co-administered: |
LEVOMEFOLIC ACID serum | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
275 ng/mL |
15 mg single, intravenous dose: 15 mg route of administration: Intravenous experiment type: SINGLE co-administered: |
LEVOMEFOLIC ACID serum | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
|
10895 ng/mL |
200 mg/m² single, intravenous dose: 200 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
LEVOLEUCOVORIN serum | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
4930 ng/mL |
200 mg/m² single, intravenous dose: 200 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
LEVOMEFOLIC ACID serum | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
1563 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8405015/ |
12.5 mg single, oral dose: 12.5 mg route of administration: Oral experiment type: SINGLE co-administered: |
LEVOMEFOLIC ACID serum | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
30719 ng × h/mL |
200 mg/m² single, intravenous dose: 200 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
LEVOLEUCOVORIN serum | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
52105 ng × h/mL |
200 mg/m² single, intravenous dose: 200 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
LEVOMEFOLIC ACID serum | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
6.8 h |
15 mg single, intravenous dose: 15 mg route of administration: Intravenous experiment type: SINGLE co-administered: |
LEVOMEFOLIC ACID serum | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
PubMed
| Title | Date | PubMed |
|---|---|---|
| Development and analysis of an in vivo-compatible metabolic network of Mycobacterium tuberculosis. | 2010-11-23 |
|
| The effect of folinic acid supplementation on homocysteine concentrations in newborns. | 2010-11 |
|
| Mutation of the proton-coupled folate transporter gene (PCFT-SLC46A1) in Turkish siblings with hereditary folate malabsorption. | 2010-11 |
|
| Properties of the Arg376 residue of the proton-coupled folate transporter (PCFT-SLC46A1) and a glutamine mutant causing hereditary folate malabsorption. | 2010-11 |
|
| Production of folate by bacteria isolated from oat bran. | 2010-09-30 |
|
| One-carbon metabolism in plants: characterization of a plastid serine hydroxymethyltransferase. | 2010-08-15 |
|
| Quantification of folate in fruits and vegetables: A fluorescence-based homogeneous assay. | 2010-07-15 |
|
| Cerebral folate deficiency presenting as adolescent catatonic schizophrenia: a case report. | 2010-07 |
|
| High-dose folate and dietary purines promote scavenging of peroxynitrite-derived radicals--clinical potential in inflammatory disorders. | 2009-11 |
|
| Role of the glutamate 185 residue in proton translocation mediated by the proton-coupled folate transporter SLC46A1. | 2009-07 |
|
| Folate in wheat genotypes in the HEALTHGRAIN Diversity Screen. | 2008-11-12 |
|
| The clinical course and genetic defect in the PCFT gene in a 27-year-old woman with hereditary folate malabsorption. | 2008-09 |
|
| The proton-coupled folate transporter: impact on pemetrexed transport and on antifolates activities compared with the reduced folate carrier. | 2008-09 |
|
| Neural tube defects and disturbed maternal folate- and homocysteine-mediated one-carbon metabolism. | 2008-08 |
|
| Investigations of the roles of arginine 115 and lysine 120 in the active site of 5,10-methenyltetrahydrofolate synthetase from Mycoplasma pneumoniae. | 2008-08 |
|
| Folate content in sea buckthorn berries and related products (Hippophaë rhamnoides L. ssp. rhamnoides): LC-MS/MS determination of folate vitamer stability influenced by processing and storage assessed by stable isotope dilution assay. | 2008-05 |
|
| Effect of folate derivatives on the activity of antifolate drugs used against malaria and cancer. | 2008-05 |
|
| pH stability of individual folates during critical sample preparation steps in prevision of the analysis of plant folates. | 2007-07-13 |
|
| Commentary: a case for minimizing folate supplementation in clinical regimens with pemetrexed based on the marked sensitivity of the drug to folate availability. | 2007-07 |
|
| Application of liquid chromatography-electrospray ionisation mass spectrometry for determination of dietary folates: effects of buffer nature and mobile phase composition on sensitivity and selectivity. | 2007-03-02 |
|
| Inhibition of 5,10-methenyltetrahydrofolate synthetase. | 2007-02-15 |
|
| Methenyltetrahydrofolate synthetase is a high-affinity catecholamine-binding protein. | 2006-11-15 |
|
| Spontaneous neural tube defects in splotch mice supplemented with selected micronutrients. | 2006-05-15 |
|
| The inverse relationship between reduced folate carrier function and pemetrexed activity in a human colon cancer cell line. | 2006-02 |
|
| Mining literature for a comprehensive pathway analysis: a case study for retrieval of homocysteine related genes for genetic and epigenetic studies. | 2006-01-23 |
|
| Higher plant plastids and cyanobacteria have folate carriers related to those of trypanosomatids. | 2005-11-18 |
|
| Structural and functional characterization of a 5,10-methenyltetrahydrofolate synthetase from Mycoplasma pneumoniae (GI: 13508087). | 2005-11-01 |
|
| The relationship between folate transport activity at low pH and reduced folate carrier function in human Huh7 hepatoma cells. | 2005-08-30 |
|
| 5-Formyltetrahydrofolate is an inhibitory but well tolerated metabolite in Arabidopsis leaves. | 2005-07-15 |
|
| Investigation of the extraction behavior of the main monoglutamate folates from spinach by liquid chromatography-electrospray ionization tandem mass spectrometry. | 2005-06-17 |
|
| Development of a simplified method for the determination of folates in baker's yeast by HPLC with ultraviolet and fluorescence detection. | 2005-04-06 |
|
| Loss of reduced folate carrier function and folate depletion result in enhanced pemetrexed inhibition of purine synthesis. | 2005-02-01 |
|
| Lack of impact of the loss of constitutive folate receptor alpha expression, achieved by RNA Interference, on the activity of the new generation antifolate pemetrexed in HeLa cells. | 2004-12-01 |
|
| Cerebral folate deficiency. | 2004-12 |
|
| Characterization of a folate transporter in HeLa cells with a low pH optimum and high affinity for pemetrexed distinct from the reduced folate carrier. | 2004-09-15 |
|
| Serine hydroxymethyltransferase: role of glu75 and evidence that serine is cleaved by a retroaldol mechanism. | 2004-06-08 |
|
| Cloning, expression, and purification of 5,10-methenyltetrahydrofolate synthetase from Mus musculus. | 2004-06 |
|
| Selective preservation of pemetrexed pharmacological activity in HeLa cells lacking the reduced folate carrier: association with the presence of a secondary transport pathway. | 2004-05-01 |
|
| Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphisms: relationships with 5-fluorouracil sensitivity. | 2004-01-26 |
|
| A prominent low-pH methotrexate transport activity in human solid tumors: contribution to the preservation of methotrexate pharmacologic activity in HeLa cells lacking the reduced folate carrier. | 2004-01-15 |
|
| 5,10-methenyltetrahydrofolate cyclohydrolase, rat liver and chemically catalysed formation of 5-formyltetrahydrofolate. | 2003-09-15 |
|
| Methenyltetrahydrofolate synthetase regulates folate turnover and accumulation. | 2003-08-08 |
|
| Uptake of 5-methyltetrahydrofolate into PC-3 human prostate cancer cells is carrier-mediated. | 2003-08 |
|
| Residues 45 and 404 in the murine reduced folate carrier may interact to alter carrier binding and mobility. | 2003-06-27 |
|
| Specific and sensitive quantification of folate vitamers in foods by stable isotope dilution assays using high-performance liquid chromatography-tandem mass spectrometry. | 2003-05 |
|
| Decreased expression of the reduced folate carrier and folypolyglutamate synthetase is the basis for acquired resistance to the pemetrexed antifolate (LY231514) in an L1210 murine leukemia cell line. | 2003-04-01 |
|
| Pyridoxal phosphate inhibits dynamic subunit interchange among serine hydroxymethyltransferase tetramers. | 2003-03-21 |
|
| Transport of 5-formyltetrahydrofolate into primary cultured cerebellar granule cells. | 2003-02-07 |
|
| Transport of 5-formyltetrahydrofolate into primary cultured rat astrocytes. | 2003-02-01 |
|
| Intrathecal leucovorin after intrathecal methotrexate overdose. | 1996-08 |
Sample Use Guides
Fusilev Rescue After High-Dose Methotrexate Therapy:
Fusilev rescue recommendations are based on a methotrexate dose of 12 grams/m2 administered by intravenous infusion over 4 hours. Fusilev rescue at a dose of 7.5 mg (approximately 5 mg/m2) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion.
Fusilev Administration in Combination with 5-Fluorouracil (5-FU):
The following regimens have been used historically for the treatment of colorectal cancer:
1. Fusilev is administered at 100 mg/m2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-FU at 370 mg/m2 by intravenous
injection.
2. Fusilev is administered at 10 mg/m by 2 intravenous injection followed by 5-FU at 425 mg/m2 by intravenous injection.
Route of Administration:
Intravenous
| Substance Class |
Chemical
Created
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Edited
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| Record UNII |
WA16A5Y52X
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| Record Status |
Validated (UNII)
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| Record Version |
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PRIMARY | RxNorm |
| Related Record | Type | Details | ||
|---|---|---|---|---|
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ANHYDROUS->SOLVATE | |||
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PARENT -> SALT/SOLVATE |
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| Related Record | Type | Details | ||
|---|---|---|---|---|
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IMPURITY -> PARENT |
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IMPURITY -> PARENT |
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| Related Record | Type | Details | ||
|---|---|---|---|---|
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ACTIVE MOIETY |
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