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Leucovorin (folinic acid) is the primary antidote for a patient who receives an overdose of methotrexate. Methotrexate prevents the conversion of inactive folic acid to the biologically active reduced form of folic acid, known as leucovorin or folinic acid. Only leucovorin is an acceptable antidote for a patient with methotrexate toxicity. Following a methanol overdose, folic acid enhances the metabolism of formate. Since methanol does not interfere with the synthesis of folinic acid, either folic acid or leucovorin is acceptable for a patient poisoned by methanol.

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Folic acid, an essential water-soluble vitamin, consists of a pteridine ring joined to PABA (para-aminobenzoic acid) and glutamic acid.7 Folic acid is the most common pharmaceutical preparation of the many folate congeners that exist in nature and perform essential cellular metabolic functions. After absorption, folic acid is reduced by dihydrofolic acid reductase (DHFR) to tetrahydrofolic acid, which accepts one-carbon groups. Tetrahydrofolic acid serves as the precursor for several biologically active forms of folic acid, including 5-formyltetrahydrofolic acid, which is best known as folinic acid, leucovorin, and citrovorum factor. These biologically active forms of folate are enzymatically interconvertible and function as cofactors, providing the one-carbon groups necessary for many intracellular metabolic reactions, including the synthesis of thymidylate and purine nucleotides, which are essential precursors of DNA.23,25,29,31,36 The minimum daily requirement of folate is normally 50 μg, but in pregnant women and nutritionally deprived, acutely ill patients, 100 to 200 μg may be required.7,8

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Methotrexate, an antimetabolite, is a structural analog of folic acid, differing only in the substitution of an amino group for a hydroxyl group at the number 4 position of the pteridine ring (see Chap. 53). Methotrexate binds to the active site of DHFR, rendering it incapable of reducing folic acid to its biologically active forms, and incapable of regenerating the necessary active forms required for the synthesis of purine nucleotides and thymidylate.30 At physiologic pH the binding between methotrexate and DHFR is competitive, with an inhibition constant of about 1 μmol/L.27 Leucovorin is a reduced, active form of folate. As such, it does not require DHFR for enzymatic interconversion to the form required for purine nucleotide and thymidylate formation. Folic acid is unable to counteract methotrexate toxicity because following methotrexate therapy, DHFR is unavailable to convert folic acid to the active reduced forms. Leucovorin rescue is the term used to describe the practice of limiting the toxic effects of high-dose methotrexate therapy.

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Monkeys experimentally made folate deficient develop methanol toxicity at lower methanol concentrations.19 Administering folic acid to normal monkeys accelerates formate metabolism.19 Pretreatment with folic acid or leucovorin decreased both formate concentrations and the accompanying metabolic acidosis, without affecting the rate of methanol elimination.19 Leucovorin remained effective in hastening the metabolism of formate when given 10 hours after methanol administration.21

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The hepatic concentrations of total ...

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