Levoleucovorin calcium pentahydrateProduct ingredient for Levoleucovorin

Name
Levoleucovorin calcium pentahydrate
Drug Entry
Levoleucovorin

Levoleucovorin is the enantiomerically active form of Folinic Acid (also known as 5-formyl tetrahydrofolic acid or leucovorin). Commercially available leucovorin is composed of a 1:1 racemic mixture of the dextrorotary and levorotary isomers, while levoleucovorin contains only the pharmacologically active levo-isomer. In vitro, the levo-isomer has been shown to be rapidly converted to the biologically available methyl-tetrahydrofolate form while the dextro form is slowly excreted by the kidneys. Despite this difference in activity, the two commercially available forms have been shown to be pharmacokinetically identical and may be used interchangeably with limited differences in efficacy or side effects (Kovoor et al, 2009).

As folate analogs, levoleucovorin and leucovorin are both used to counteract the toxic effects of folic acid antagonists, such as methotrexate, which act by inhibiting the enzyme dihydrofolate reductase (DHFR). They are indicated for use as rescue therapy following use of high-dose methotrexate in the treatment of osteosarcoma or for diminishing the toxicity associated with inadvertent overdosage of folic acid antagonists. Levoleucovorin, as the product Fusilev (FDA), has an additional indication for use in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer.

Folic acid is an essential B vitamin required by the body for the synthesis of purines, pyrimidines, and methionine before incorporation into DNA or protein. However, in order to function in this role, it must first be reduced by the enzyme dihydrofolate reductase (DHFR) into the cofactors dihydrofolate (DHF) and tetrahydrofolate (THF). This important pathway, which is required for de novo synthesis of nucleic acids and amino acids, is disrupted when high-dose methotrexate is used for cancer therapy. As methotrexate functions as a DHFR inhibitor to prevent DNA synthesis in rapidly dividing cells, it also prevents the formation of DHF and THF. This results in a deficiency of coenzymes and a resultant buildup of toxic substances that are responsible for numerous adverse side effects of methotrexate therapy. As levoleucovorin and leucovorin 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.

Accession Number
DBSALT001887
Structure
Synonyms
Calcium levofolinate pentahydrate
UNII
WA16A5Y52X
CAS Number
419573-16-3
Weight
Average: 601.583
Monoisotopic: 601.1656604
Chemical Formula
C20H31CaN7O12
InChI Key
NPPBLUASYYNAIG-BWDMFOMUSA-L
InChI
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
IUPAC Name
calcium (4S)-4-carboxy-4-{[4-({[(6S)-5-formyl-2-imino-4-oxido-1,2,5,6,7,8-hexahydropteridin-6-yl]methyl}amino)phenyl]formamido}butanoate pentahydrate
SMILES
O.O.O.O.O.[Ca++].[H][C@@](CCC([O-])=O)(NC(=O)C1=CC=C(NC[C@@]2([H])CNC3=C(N2C=O)C([O-])=NC(=N)N3)C=C1)C(O)=O
ChemSpider
2006560
Predicted Properties
PropertyValueSource
Water Solubility0.168 mg/mLALOGPS
logP0.58ALOGPS
logP-1.9Chemaxon
logS-3.5ALOGPS
pKa (Strongest Acidic)3.49Chemaxon
pKa (Strongest Basic)2.87Chemaxon
Physiological Charge-2Chemaxon
Hydrogen Acceptor Count12Chemaxon
Hydrogen Donor Count6Chemaxon
Polar Surface Area222.2 Å2Chemaxon
Rotatable Bond Count9Chemaxon
Refractivity158.86 m3·mol-1Chemaxon
Polarizability45.47 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon