Chapter A12: Folates: Leucovorin (Folinic Acid) and Folic Acid

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 (MTX), pyrimethamine and pemetrexed prevent this reduction. Leucovorin (folinic acid) and levoleucovorin, do not require dihydrofolate reductase for activation. Therefore, either leucovorin or levoleucovorin is the primary antidote for a patient who receives an overdose of MTX 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. Preliminary evidence also suggests a role for folic acid to enhance arsenic elimination.

HISTORY

In 1930–1931, Lucy Wills, while studying pregnant textile workers with macrocytic anemia in Mumbai, India, discovered that a yeast extract provided to these nutritionally deficient individuals cured and prevented their anemia.¹⁰⁵ Mitchell isolated the active ingredient from spinach in 1941 and named it folic acid from the Latin folium, meaning leaf.³⁵ Subsequently, the synthesis and chemical structure of folate was described in 1945–1946.³ In 1948, the first reported clinical success in inducing temporary remission of acute leukemia by the antifolate aminopterin was reported, soon followed by success with the less toxic amethopterin (ie, MTX).²⁴ That same year, in studies exploring links to anemia, a factor in the gram-positive bacteria Leuconostoc citrovorum was identified as required in growth media for deficient species.⁷⁹ Two years later in 1950, this “citrovorum factor”—later named leucovorin (folinic acid)—successfully reversed aminopterin and MTX toxicity, which had resisted folate therapy.⁸² In the 1960s, the concept emerged of providing higher doses of MTX for improved chemotherapeutic efficacy, which was then coupled with subsequent leucovorin “rescue” to mitigate toxicity.⁵³ 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.³ Folic acid is the most common of the many folate congeners that exist in nature and are essential for normal cellular metabolic functions. Folic acid is rarely 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. The biologically active forms of folate are enzymatically interconvertible and function as ...