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Calcium folinatc(CAS No. 1492-18-8)

Calcium folinatc C20H21CaN7O7 (cas 1492-18-8) Molecular Structure

1492-18-8 Structure

Identification and Related Records

【Name】
Calcium folinatc
【CAS Registry number】
1492-18-8
【Synonyms】
Folinic acid Calcium salt
calcium folinate
Folinic acid calcium salt USP28
Calcium leucovorin
LeucovorinCalcium
CALCIUM FOLINATE(FOLINIC ACID)(RG)
Folinic acid
Calcium Levofolinate
Leucovorin Calcium
calcium2-[4-[(2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl] aminopentanedioate
L-Calcium Folinate
【EINECS(EC#)】
216-082-8
【Molecular Formula】
C20H21CaN7O7 (Products with the same molecular formula)
【Molecular Weight】
511.5
【Inchi】
InChI=1/C20H23N7O7.Ca/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/p-2/t12?,13-;/m0./s1
【Canonical SMILES】
C1C(N(C2=C(N1)NC(=NC2=O)N)C=O)CNC3=CC=C(C=C3)C(=O)NC(CCC(=O)O)C(=O)O
【Isomers smiles】
C1C(N(C2=C(N1)NC(=NC2=O)N)C=O)CNC3=CC=C(C=C3)C(=O)N[C@H](CCC(=O)O)C(=O)O
【MOL File】
1492-18-8.mol

Chemical and Physical Properties

【Appearance】
yellow crystalline powder
【Density】
g/cm3
【Melting Point】
240-250
【Boiling Point】
°Cat760mmHg
【Flash Point】
°C
【Solubilities】
Sparingly soluble in water
【Color/Form】
Crystals from water with 3 mol of water of crystallization.
【Stability】
Stable at normal temperatures in tightly closed containers under an inert atmosphere.
【Storage temp】
Store in a tightly closed container. Keep under an argon blanket. Store in a cool, dry, well-ventilated area away from incompatible substances. Refrigerator (approx 4 C). Store protected from light and air.
【Spectral properties】
Specific optical rotation: +16.76 deg at 25 deg C/D (5% sodium carbonate, concentration = 3.5%).
UV: 1-870 (Philip et al., Organic Electronic Spectral Data, John Wiley & Sons, New York)
【Computed Properties】
Molecular Weight:473.43932 [g/mol]
Molecular Formula:C20H23N7O7
XLogP3-AA:-1.2
H-Bond Donor:7
H-Bond Acceptor:9
Rotatable Bond Count:9
Tautomer Count:85
Exact Mass:473.165896
MonoIsotopic Mass:473.165896
Topological Polar Surface Area:216
Heavy Atom Count:34
Formal Charge:0
Complexity:911
Isotope Atom Count:0
Defined Atom Stereocenter Count:1
Undefined Atom Stereocenter Count:1
Defined Bond Stereocenter Count:0
Undefined Bond Stereocenter Count:0
Covalently-Bonded Unit Count:1
Feature 3D Acceptor Count:7
Feature 3D Donor Count:6
Feature 3D Anion Count:2
Feature 3D Cation Count:2
Feature 3D Ring Count:3
Effective Rotor Count:11.8
Conformer Sampling RMSD:1.2
CID Conformer Count:118

Safety and Handling

【Hazard Codes】
Xn:Harmful
【Risk Statements】
R36/37/38;R42/43
【Safety Statements 】
S26;S36
【Safety】

Hazard Codes:?HarmfulXn
Risk Statements about Folinic acid (CAS No.1492-18-8):
R42/43: May cause sensitization by inhalation and skin contact.?
R36/37/38: Irritating to eyes, respiratory system and skin.
Safety Statements:
S22: Do not breathe dust.?
S26: In case of contact with eyes, rinse immediately with plenty of water and seek medical advice.?
S36: Wear suitable protective clothing.?
S36/37: Wear suitable protective clothing and gloves.
Attention:
1. Storage: Store in a tightly closed container. Keep under an argon blanket. Store in a cool, dry, well-ventilated area away from incompatible substances. Refrigerator (approx 4 °C). Store protected from light and air.
2. Handling: Wash hands before eating. Use only in a well ventilated area. Avoid breathing dust, vapor, mist, or gas. Avoid contact with skin and eyes. Keep container tightly closed. Store protected from light. Use and store under nitrogen. Store and handle protected from air. Wash clothing before reuse. Discard contaminated shoes.

【Transport】
OTH
【Formulations/Preparations】
Tablets, 5, 10, 15, and 25 mg. Powder for oral solution, 1 mg, following reconstitution. Ampules, 3 mg/ml and 5 mg/ml. Vials, 50, 100, and 350 mg. /Leucovorin calcium/
Oral Tablets, 5 mg (of leucovorin), Wellcovorin (with povidone; scored), Burroughs Wellcome; 10 mg (of leucovorin), Leucovorin Calcium Tablets (scored), Lederle; 15 mg (of leucovorin), Leucovorin Calcium Tablets (scored), Lederle; 25 mg (of leucovorin), Wellcovorin (with povidone; scored), Burroughs Wellcome; Parenteral For Injection, 50 mg (of leucovorin), Leucovorin Calcium for Injection, Cetus, Elkins-Sinn, Lederle; 100 mg (of leucovorin), Leucovorin Calcium for Injection, Cetus, Lederle; Wellcovorin, Burroughs Wellcome; 350 mg (of leucovorin), Leucovorin Calcium for Injection, Lederle; Injection, 3 mg (of leucovorin) per ml, Leucovorin Calcium Injection (with benzyl alcohol 0.9%), Lederle. /Leucovorin calcium/
【Exposure Standards and Regulations】
The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl leucovorin calcium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Leucovorin Calcium/
【Specification】

? Folinic acid (CAS No.1492-18-8), generally administered as calcium folinate (or leucovorin calcium), is an adjuvant used in cancer chemotherapy involving the drug methotrexate.It is also used in synergistic combination with the chemotherapy agent 5-fluorouracil.It is administered at the appropriate time following methotrexate as part of a total chemotherapeutic plan, where it may "rescue" bone marrow and gastrointestinal mucosa cells from methotrexate. There is no apparent effect on preexisting methotrexate-induced nephrotoxicity.While not specifically an antidote for methotrexate, folinic acid may also be useful in the treatment of acute methotrexate overdose. Different dosing protocols are used, but folinic acid should be re-dosed until the methotrexate level is less than 5 x 10-8 M.It is also used in combination with the chemotherapy agent 5-fluorouracil in treating colon cancer. In this case, folinic acid is not used for "rescue" purposes ; rather, it enhances the effect of 5-fluorouracil by inhibiting thymidylate synthase.

【Octanol/Water Partition Coefficient】
log Kow = -4.45 /Estimated/
【Disposal Methods】
SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

Use and Manufacturing

【Use and Manufacturing】
Methods of Manufacturing

(1) Prepared by catalytic reduction of folic acid, (2) produced microbially.
Manufactoring: Shive, US 2741608 (1956 to Res. Corp.)
【Usage】

An adjuvant used in cancer chemotherapy involving the drug methotrexate.

Biomedical Effects and Toxicity

【Pharmacological Action】
- A group of water-soluble vitamins, some of which are COENZYMES.
【Therapeutic Uses】
Leucovorin is indicated for use in combination with agents such as fluorouracil or high-dose methotrexate, as second-line treatment of squamous cell head and neck carcinoma. /NOT included in US product labeling/
Antidotes
Leucovorin is indicated as a antidote to the toxic effects of folic acid antagonists such as methotrexate, pyrimethamine, or trimethoprim. Leucovorin also is indicated as a rescue after high-dose methotrexate therapy in osteosarcoma and as a part of chemotherapeutic treatment programs in the management of several forms of cancer. /Included in US product labeling/
Leucovorin is indicated to treat megaloblastic anemias associated with sprue, nutritional deficiency, pregnancy, and infancy when oral folic acid therapy is not feasible. Leucovorin is not recommended for use in the treatment of pernicious anemia or other megaloblastic anemias secondary to lack of vitamin B12, since it may produce a hematologic remission while neurologic manifestations continue to progress. /Included in US product labeling/
Leucovorin is indicated for use in combination with fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer. /Included in US product labeling/
Leucovorin is indicated for use in combination with agents such as fluorouracil or high-dose methotrexate, as second-line treatment of Ewing's sarcoma and non-Hodgkin's lymphomas. /NOT included in US product labeling/
Leucovorin is indicated for use in combination with high-dose methotrexate as second-line treatment of gestational trophoblastic neoplasms. /NOT included in US product labeling/
【Biomedical Effects and Toxicity】
Duration of action: All routes: 3 to 6 hours.
Onset of action: Oral: 20 to 30 minutes. Intramuscular: 10 to 20 minutes. Intravenous: Less than 5 minutes.
Crosses blood-brain barrier in moderate amounts; largely concentrated in liver.
Elimination: Renal: 80-90%. Fecal: 5-8%.
Normal total serum folate concentrations have been reported to range from 0.005-0.015 ug/mL. Folate is actively concentrated in CSF, and normal CSF concentrations are reported to be about 0.016 0.021 ug/mL. Normal erythrocyte folate concentrations range from 0.175-0.316, ug/mL. In general, serum folate concentrations less than 0.005 ug/mL indicate folate deficiency and concentrations less than 0.002 ug/mL usually result in megaloblastic anemia. Following im administration of a 15 mg (7.5 mg/sq m) dose in healthy men, mean peak serum folate concentrations of 0.241 ug/mL occur within about 40 minutes. Following oral administration of a 15 mg (7.5 mg/sq m) dose in healthy men, mean peak serum folate concentrations of 0.268 ug/mL occur within about 1.72 hr. Areas under the serum folate concentration-time curves are reported to be about 8% less following im injection in the gluteal region than in the deltoid region and about 12% less following im injection in the gluteal region than following iv or oral administration.
Tetrahydrofolic acid and its derivatives are distributed to all body tissues; the liver contains about one-half of total body folate stores. In a small number of patients, biliary concentration of folates was about 4.5 times the plasma folate concentration after oral administration of a 2 mg dose of leucovorin; this is believed to represent the hepatic folate pool rather than excretion of the administered dose.
Leucovorin is excreted in urine, mainly as 10-formyl tetrahydrofolate and 5,10-methenyl tetrahydrofolate. There is some evidence that 5-methyl tetrahydrofolate may be conserved by the kidneys in preference to 5-formyl tetrahydrofolate (leucovorin). Loss of folate in the urine becomes approximately logarithmic as the amount of leucovorin administered exceeds 1 mg.
A randomized, crossover study was conducted to determine the pharmacokinetics of leucovorin calcium after iv, im and oral administration in 37 healthy men of a single 25 mg dose of leucovorin calcium, either reconstituted with bacteriostatic water for injection for iv and im dosing or with aromatic elixir for oral administration. Bioavailability and bioequivalence were assessed by measuring over 24 hr the blood concentrations of total folates, the parent cmpd 5-formyltetrahydrofolate (leucovorin), and the metabolite 5-methyltetrahydrofolate (methyltetrahydrofolate). Both iv and im administration produced rapid serum rises in biologically active folates; these rises were sustained over time and were still detectable at 24 hr after drug administration. Iv and im administration were bioequivalent based on area under the serum concentration time curve, although for im administration, the peak concentration was lower and the time to peak concentration was longer. The initial rise in serum folates with iv and im dosing represented leucovorin which fell concomitantly with the appearance of methyltetrahydrofolate. Oral administration, 92% bioavailable compared with iv administration, produced a predictably different pattern of circulating folates, methyltetrahydrofolate being the predominant form. Terminal elimination half life, apparent volume of distribution and clearance of total folates were not significantly different among the 3 treatments. /Leucovorin calcium/ [McGuire BW et al; Clin Pharm 7 (Jan): 52-8 (1988)] PubMed Abstract
It is not known whether leucovorin is distributed into breast milk.
Rapidly absorbed after oral administration; saturation of absorption is reached at doses greater than 25 mg. Bioavailability is approximately 97% for a 25 mg dose, 75% for a 50 mg dose, and 37% for a 100 mg dose.

Environmental Fate and Exposure Potential

【Environmental Fate/Exposure Summary】
TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1,500(SRC), determined from a structure estimation method(2), indicates that leucovorin is expected to have low mobility in soil(SRC). The pKa values of leucovorin are 3.5 and 4.5 for the carboxylic acids moieties and 10.3 for the amino group(3), indicating that this compound will primarily exist as two anions and one cation in the environment and charged species do not volatilize from moist soil surfaces. Leucovorin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.3X10-21 mm Hg(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2005).
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1,500(SRC), determined from a structure estimation method(2), indicates that leucovorin is expected to adsorb to suspended solids and sediment(SRC). The pKa values of leucovorin are 3.1, 4.8 for the carboxylic acid moieties and 10.3 for the amine(3), indicating that this compound will primarily exist as two anions and one cation in the environment and charged species do not volatilize from water surfaces. According to a classification scheme(4), an estimated BCF of 3.2(SRC), from an estimated log Kow of -4.5(5) and a regression derived equation(6) suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2005).
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), leucovorin, which has an estimated vapor pressure of 2.3X10-21 mm Hg at 25 deg C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase leucovorin may be removed from the air by wet and dry deposition(SRC). Leucovorin does not absorb UV light >290 nm(3); therefore leucovorin should not be susceptible to photolysis(SRC).

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