Drug-Induced Folate Deficiency

The mechanism of this drug-induced folic acid deficiency is not clear, although a number of effects have been reported  

DiphenyUiydantoin and other anticonvulsants impair the intestinal absorption of folates. This may be by inhibition of intestinal conjugase however, the evidence from various studies is conflicting. 

DiphenyUiydantoin causes an increased rate of catabolism of folate and increased excretion of folate metabolites (KeUy et al., 1979). 

Chronic therapy of experimental animals with primidone depletes liver folate pentaglutamates, suggesting inhibition of folate polyglutamate synthetase (Carl et al 1987). This would be expected to lead to increased excretion of folate metabolites. 

Administration of diphenylhydantoin leads to decreased activity of methylene tetrahydrofolate reductase and an increased rate of oxidation of formyl tetrahydrofolate (increased oxidation of formate and histidine), with a fall in methylene- and methyl-tetrahydrofolate - the reverse of the effect of the methyl folate trap (Billings, 1984a, 1984b). 

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Oral use of sulfonamides, pyrimethamine, and trimethoprim can canse blood dyscrasias such as hemolytic anemia, aplastic anemia, lenkopenia, and agran-nlocytosis. Becanse these blood changes are due to a drug-induced folic acid deficiency, administering folinic (not folic) acid can coimteract the toxicity. Use of folinic acid bypasses the need fc>r dihydrofolate reductase by supplying the fully reduced folate. 

The resnlts of folic acid measnrements may vary depending on the assay method nsed. Decreased serum folic acid levels indicate a folate deficiency megaloblastic anemia that may coexist with a vitamin B12 deficiency anemia. An erythrocyte folic acid level is less volatile than sernm levels, as it is slow to decrease in an acnte process such as drug-induced folic acid deficiency, and slow to increase with oral folic acid replacement. However, the clinical ntflity of determining the erythrocyte folic acid level is qnestionable, and the procedure should be reserved for cases in which the clinician snspects folic acid depletion and the serum folic acid may be falsely elevated or depleted. 

Several drugs (e.g., sulfasalazine, trimethoprim-sulfamethoxazole, and methotrexate) have been reported to cause a fohc acid deficiency megaloblastic anemia. These drugs either interfere with folate absorption or inhibit the dihydrofolate reductase enzyme necessary for conversion of dihydrofolate to its active tetrahydrofolate form (see Chap. 102, on drug-induced blood dyscrasias). 

The dihydrofolate reductase inhibitor, methotrexate (Fig. 8.47), was developed as an anticancer drug, whose inhibition of formation of folic acid coenzymes would block purine synthesis. In other words, it was designed to induce a folic acid deficiency. Notice in Figs. 8.50 and 8.51 that formation of dTMP, FGAR, and AICAR also causes the oxidation of tetra-hydrofolate to dihydrofolate. The latter must be reduced by dihydrofolate reductase to tet-rahydrofolate before active coenzyme can form again. Thus, not only does methotrexate inhibit the initial formation of the tetrahydro-folate moiety, it blocks regeneration of the coenzyme form. 

Antiepileptic drugs, primarily those with inducer effects on liver enzyme activity, may cause a low folate status with risk of deficiency. Antiepileptic drugs may be associated with low levels of vitamins Bg and B2, but vitamin B12 is usually within normal range. 

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