Malabsorption of Folic Acid due to Diphenylhydantoin

Abstract

A high incidence of subnormal serum folate levels in pediatric subjects receiving diphenylhydantoin is reported. The effect is observed shortly after the onset of therapy and is not related to dosage of drug. An adult epileptic, who presented with a megaloblastic anemia secondary to a diphenylhydantoin-induced folate deficiency, demonstrated normal serum and erythrocyte folate levels only after folic acid was administered orally in amounts of 600 µg. per day. The folate deficiency was due to malabsorption of folic acid induced by diphenylhydantoin. Folic acid tolerance tests performed at 0, 4, 12, 16 and 20 hours after diphenylhydantoin showed a progressive rise in serum levels as diphenylhydantoin was withheld for longer periods prior to the test dose of folic acid. Further evidence of improved absorption was an associated rise in urinary folates. In addition, the patient demonstrated a convincing hematologic response to ingested conjugase, in the form of chick pancreas. The hematologic response was observed, despite prior demonstration of conjugase activity in the patient’s intestinal secretions. Attempts to show inhibition of chick pancreas conjugase activity by diphenylhydantoin in vitro were unsuccessful. Several explanations for these conflicting observations are offered.