A10: Antidotes in Depth

INTRODUCTION

Folates refer to the metabolically active reduced forms of folic acid, including dihydrofolate and tetrahydrofolate. These folates are vital to cellular biochemistry, including the synthesis of purines and DNA. Folic acid must be reduced in vivo by dihydrofolate reductase to tetrahydrofolate. Dihydrofolate reductase inhibitors such as methotrexate prevent this reduction. Leucovorin (folinic acid) and levoleucovorin, and compared with folic acid, they do not require dihydrofolate reductase for activation. Therefore, either leucovorin or levoleucovorin is the primary antidote for a patient who receives an overdose of methotrexate or another dihydrofolate reductase inhibitor.

Methanol is metabolized to the active and toxic formic acid. Folates, including folic acid and leucovorin, speed up the conversion of formic acid to nontoxic metabolites. Because methanol does not interfere with the synthesis of tetrahydrofolate, either folic acid or leucovorin is acceptable for a patient poisoned by methanol who necessitates enhanced formate metabolism. Preliminary evidence also suggests a role for folic acid to enhance ­arsenic elimination.

HISTORY

In the early 1930s when Lucy Wills went to Bombay to study pregnant textile workers with macrocytic anemia, she found that a yeast extract given to these poor people with a nutritionally deficient diet corrected and prevented their anemia.¹¹ Mitchell isolated the active ingredient from spinach in 1941 and named it folic acid from the Latin folium meaning leaf.¹¹ Subsequently, folic acid was synthesized and its chemical structure identified. Since then, the many roles of folate and natural or induced folate deficiency continue to be studied.

PHARMACOLOGY

Folic acid (pteroylglutamic acid), an essential water-soluble vitamin, consists of a pteridine ring joined to PABA (para-aminobenzoic acid) and glutamic acid.¹⁰ Folic acid is the most common of the many folate congeners that exist in nature and perform essential cellular metabolic functions. Folic acid is often called vitamin B₉. After absorption, folic acid is reduced by dihydrofolic acid reductase (DHFR) to dihydrofolic acid and then tetrahydrofolic acid (THF), which accepts one carbon groups. Tetrahydrofolic acid serves as the precursor for several biologically active forms of folic acid, including 5-formyltetrahydrofolic acid (5-formyl THF), 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.^{29,32,36,38,43} The minimum daily requirement of folic acid is normally 50 µg, but pregnant women and nutritionally deprived, acutely ill patients may require 100 to 200 µg.^10,12

Leucovorin is a mixture of the active and inactive diastereoisomers of 5-formyl THF of which the levo form is active and available as ­levoleucovorin.⁶ Both are available as the calcium salt, with the same chemical formula, ...