Folinic acid

Folinic acid

Systematic (IUPAC) name
(S)-2-[4-[(2-amino-5-formyl-4-oxo-5,6,7,8- tetrahydro-1H-pteridin-6-yl)methylamino] benzoyl]aminopentanedioic acid
Identifiers
CAS number	1492-18-8
ATC code	V03AF03
PubChem	54575
DrugBank	APRD00698
Chemical data
Formula	C20H23N7O7
Mol. mass	473.44 g/mol
Pharmacokinetic data
Bioavailability	Dose dependent: 97% (25mg) 75% (50mg) 37% (100mg)
Protein binding	~15%
Metabolism	?
Half life	6.2 hours
Excretion	Urinary
Therapeutic considerations
Pregnancy cat.	A(AU) C(US)
Legal status
Routes	Intravenous, oral
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Levofolinic acid

Folinic acid (INN) or leucovorin (USAN), generally administered as calcium or sodium folinate (or leucovorin calcium/sodium), is an adjuvant used in cancer chemotherapy involving the drug methotrexate.^[1] It is also used in synergistic combination with the chemotherapy agent 5-fluorouracil.

Levofolinic acid and its salts are the enantiopure drugs. They are configurated S at the remaining asymmetric carbon atom (see below).

Folinic acid should be distinguished from folic acid.

Mechanism of action

Folinic acid is a 5-formyl derivative of tetrahydrofolic acid. It is readily converted to other reduced folic acid derivatives (e.g. tetrahydrofolate), and thus has vitamin activity which is equivalent to folic acid. However, since it does not require the action of dihydrofolate reductase for its conversion, its function as a vitamin is unaffected by inhibition of this enzyme by drugs such as methotrexate.

Folinic acid, therefore, allows for some purine/pyrimidine synthesis to occur in the presence of dihydrofolate reductase inhibition, so that some normal DNA replication and RNA transcription processes can proceed.

Therapeutic use

Folinic acid 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.^[2]

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^[3]

Folinic acid 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.

Folinic acid is also sometimes used to prevent toxic effects of high doses of antimicrobial dihydrofolate reductase inhibitors such as trimethoprim and pyrimethamine.

Folinic acid has dextro- and levo-isomers, only the latter one being pharmacologically useful. As such, Levoleucovorin was approved by the FDA in 2008.^[4]

It has been investigated for use in Down's syndrome, but a benefit has not been demonstrated.^[5]

Note on administration

Folinic acid should not be administered intrathecally. This may produce severe adverse effects or even death.^[6]

References