Details
| Stereochemistry | ABSOLUTE |
| Molecular Formula | C20H21N7O7.2Na |
| Molecular Weight | 517.403 |
| Optical Activity | UNSPECIFIED |
| Defined Stereocenters | 2 / 2 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
[Na+].[Na+].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=FSDMNNPYPVJNAT-NJHZPMQHSA-L
InChI=1S/C20H23N7O7.2Na/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);;/q;2*+1/p-2/t12-,13-;;/m0../s1
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 |
|---|---|---|---|---|
10895 ng/mL |
200 mg/m² single, intravenous dose: 200 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
LEVOLEUCOVORIN unknown | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
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 |
|
4930 ng/mL |
200 mg/m² single, intravenous dose: 200 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
LEVOMEFOLIC ACID unknown | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
30719 ng × h/mL |
200 mg/m² single, intravenous dose: 200 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
LEVOLEUCOVORIN unknown | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
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 |
|
52105 ng × h/mL |
200 mg/m² single, intravenous dose: 200 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
LEVOMEFOLIC ACID unknown | 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 |
Doses
| Dose | Population | Adverse events |
|---|---|---|
250 mg/m2 1 times / 2 weeks multiple, intravenous Higher than recommended Dose: 250 mg/m2, 1 times / 2 weeks Route: intravenous Route: multiple Dose: 250 mg/m2, 1 times / 2 weeks Co-administed with:: irinotecan, i.v(200 mg/m2) Sources: Page: p.2075-fluorouracil, i.v(850 mg/m2) |
unhealthy, 39 n = 254 Health Status: unhealthy Condition: Colorectal cancer Age Group: 39 Sex: M+F Population Size: 254 Sources: Page: p.207 |
Other AEs: Neutropenia... |
300 mg/m2 1 times / day multiple, intravenous Highest studied dose Dose: 300 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 300 mg/m2, 1 times / day Co-administed with:: etoposide, i.v(100 mg/m2/day; days 2-4) Sources: Page: p.3205-fluorouracil, i.v(500 mg/m2/day; days 1-5) |
unhealthy, 66 n = 36 Health Status: unhealthy Condition: Gastric cancer Age Group: 66 Sex: M+F Population Size: 36 Sources: Page: p.320 |
Other AEs: Leucopenia... |
AEs
| AE | Significance | Dose | Population |
|---|---|---|---|
| Neutropenia | grade 4, 15% | 250 mg/m2 1 times / 2 weeks multiple, intravenous Higher than recommended Dose: 250 mg/m2, 1 times / 2 weeks Route: intravenous Route: multiple Dose: 250 mg/m2, 1 times / 2 weeks Co-administed with:: irinotecan, i.v(200 mg/m2) Sources: Page: p.2075-fluorouracil, i.v(850 mg/m2) |
unhealthy, 39 n = 254 Health Status: unhealthy Condition: Colorectal cancer Age Group: 39 Sex: M+F Population Size: 254 Sources: Page: p.207 |
| Leucopenia | grade 4 | 300 mg/m2 1 times / day multiple, intravenous Highest studied dose Dose: 300 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 300 mg/m2, 1 times / day Co-administed with:: etoposide, i.v(100 mg/m2/day; days 2-4) Sources: Page: p.3205-fluorouracil, i.v(500 mg/m2/day; days 1-5) |
unhealthy, 66 n = 36 Health Status: unhealthy Condition: Gastric cancer Age Group: 66 Sex: M+F Population Size: 36 Sources: Page: p.320 |
PubMed
| Title | Date | PubMed |
|---|---|---|
| Intrathecal leucovorin after intrathecal methotrexate overdose. | 1996 Aug |
|
| Lack of catalytic activity of a murine mRNA cytoplasmic serine hydroxymethyltransferase splice variant: evidence against alternative splicing as a regulatory mechanism. | 2001 Apr 24 |
|
| Re-evaluation of the metabolism of oral doses of racemic carbon-6 isomers of formyltetrahydrofolate in human subjects. | 2001 Jun |
|
| Ontogeny of hepatic enzymes involved in serine- and folate-dependent one-carbon metabolism in rabbits. | 2001 May |
|
| Mitochondria from cultured cells derived from normal and thiamine-responsive megaloblastic anemia individuals efficiently import thiamine diphosphate. | 2002 Apr 25 |
|
| Role of the C-terminus and the long cytoplasmic loop in reduced folate carrier expression and function. | 2002 May 1 |
|
| Transport of 5-formyltetrahydrofolate into primary cultured cerebellar granule cells. | 2003 Feb 7 |
|
| Residues 45 and 404 in the murine reduced folate carrier may interact to alter carrier binding and mobility. | 2003 Jun 27 |
|
| 5,10-methenyltetrahydrofolate cyclohydrolase, rat liver and chemically catalysed formation of 5-formyltetrahydrofolate. | 2003 Sep 15 |
|
| 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 Dec 1 |
|
| 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 Jan 15 |
|
| Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphisms: relationships with 5-fluorouracil sensitivity. | 2004 Jan 26 |
|
| Serine hydroxymethyltransferase: role of glu75 and evidence that serine is cleaved by a retroaldol mechanism. | 2004 Jun 8 |
|
| Selective preservation of pemetrexed pharmacological activity in HeLa cells lacking the reduced folate carrier: association with the presence of a secondary transport pathway. | 2004 May 1 |
|
| Development of a simplified method for the determination of folates in baker's yeast by HPLC with ultraviolet and fluorescence detection. | 2005 Apr 6 |
|
| Loss of reduced folate carrier function and folate depletion result in enhanced pemetrexed inhibition of purine synthesis. | 2005 Feb 1 |
|
| 5-Formyltetrahydrofolate is an inhibitory but well tolerated metabolite in Arabidopsis leaves. | 2005 Jul 15 |
|
| Investigation of the extraction behavior of the main monoglutamate folates from spinach by liquid chromatography-electrospray ionization tandem mass spectrometry. | 2005 Jun 17 |
|
| The inverse relationship between reduced folate carrier function and pemetrexed activity in a human colon cancer cell line. | 2006 Feb |
|
| Mining literature for a comprehensive pathway analysis: a case study for retrieval of homocysteine related genes for genetic and epigenetic studies. | 2006 Jan 23 |
|
| Methenyltetrahydrofolate synthetase is a high-affinity catecholamine-binding protein. | 2006 Nov 15 |
|
| Neural tube defects and disturbed maternal folate- and homocysteine-mediated one-carbon metabolism. | 2008 Aug |
|
| Investigations of the roles of arginine 115 and lysine 120 in the active site of 5,10-methenyltetrahydrofolate synthetase from Mycoplasma pneumoniae. | 2008 Aug |
|
| 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 May |
|
| Folate in wheat genotypes in the HEALTHGRAIN Diversity Screen. | 2008 Nov 12 |
|
| The clinical course and genetic defect in the PCFT gene in a 27-year-old woman with hereditary folate malabsorption. | 2008 Sep |
|
| The proton-coupled folate transporter: impact on pemetrexed transport and on antifolates activities compared with the reduced folate carrier. | 2008 Sep |
|
| Role of the glutamate 185 residue in proton translocation mediated by the proton-coupled folate transporter SLC46A1. | 2009 Jul |
|
| High-dose folate and dietary purines promote scavenging of peroxynitrite-derived radicals--clinical potential in inflammatory disorders. | 2009 Nov |
|
| One-carbon metabolism in plants: characterization of a plastid serine hydroxymethyltransferase. | 2010 Aug 15 |
|
| Cerebral folate deficiency presenting as adolescent catatonic schizophrenia: a case report. | 2010 Jul |
|
| Quantification of folate in fruits and vegetables: A fluorescence-based homogeneous assay. | 2010 Jul 15 |
|
| The effect of folinic acid supplementation on homocysteine concentrations in newborns. | 2010 Nov |
|
| Mutation of the proton-coupled folate transporter gene (PCFT-SLC46A1) in Turkish siblings with hereditary folate malabsorption. | 2010 Nov |
|
| Properties of the Arg376 residue of the proton-coupled folate transporter (PCFT-SLC46A1) and a glutamine mutant causing hereditary folate malabsorption. | 2010 Nov |
|
| Development and analysis of an in vivo-compatible metabolic network of Mycobacterium tuberculosis. | 2010 Nov 23 |
|
| Production of folate by bacteria isolated from oat bran. | 2010 Sep 30 |
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
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DBSALT001890
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100000134700
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1141892-29-6
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ACTIVE MOIETY
SUBSTANCE RECORD
