calcium leucovorin

rev 7/12/24

Calcium leucovorin

Main use

Leucovorin calcium is a medication used to decrease the toxic effects of methotrexate (methotrexate was first developed in the 1950s as a cancer treatment and is still used for this in higher doses.) . Leucovoein is also used in combination with 5 fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to treat folate deficiency that results in anemia and methanol poisoning .

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 .

As folate analogs, leucovorin and levoleucovorin are both used to counteract the toxic effects of folic acid antagonists, such as methotrexate, which act by inhibiting the enzyme cijydrofolate 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. Injectable forms are also indicated for use in the treatment of megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible and for use in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer.

Calcium leucovorin is produced in 4 chemical steps starting from folic acid .Folic acid is formylated by formic acid , the formyl derivative being hydrogenated at 20°c with Pt or Pd catalyst .

The product is then trnsformed into hdrochloride form which is isolated and purified (charcoal treatment + cristallisation) .

The purified hydrochloride is transformed in calcium leucovorin by action of calcium hydroxyde to give a crude calcium leucovorin which is isolated by cristallisation

The crude calcium leucovorin is purified by percholation through a selected adsorbant and crystallised to get the final product

The final product is sold under various forms ( injection or tablet)

Main producers

Pfizer - A prominent pharmaceutical company that produces leucovorin under various brand names.
    Hikma Pharmaceuticals - Manufactures leucovorin in different dosages and forms, including injectables.
    Fresenius Kabi - Offers leucovorin for injection, often used in hospitals and clinics.
    Teva Pharmaceuticals - Produces generic versions of leucovorin calcium.
    Sandoz (a division of Novartis) - Known for generic drug manufacturing, including leucovorin.
    Amneal Pharmaceuticals - Provides leucovorin as part of its generic drug portfolio.

General process info

Leucovorin from folic acid

JACS 1952 vol74 Synthesis of Leucovorin fromfolicacid p 3247 Lederle Laboratories (division American Cyanamid)
US patent US2741608 april 1956 : examples of synthesis from folic acid
US patent US4500711 feb 1985: example of synthesis from anhydroleucovorine with organic amine

US5010194A * 1988-11-11 1991-04-23 Eprova Ag Method for the resolution of folinic acid

US5173488A * 1989-08-21 1992-12-22 American Cyanamid Company Stable injectable pharmaceutical formulation for folic acid and leucovorin salts and method

US5334535A * 1989-12-11 1994-08-02 American Cyanamid Company Process for the preparation of optically pure diastereoisomers of tetrahydrofolate compounds using 10-formyltetrahydrofolate synthetase from clostridium

US5599931A * 1992-02-20 1997-02-04 Bracco S.P.A. Process for separating stereoisomers of folinic acid

US5710271A * 1994-06-08 1998-01-20 Dibra S.P.A. Process for the preparation and separation of diastereomeric salts of folinic acid

Folic acid from scratch