PHENYTOIN-FOLIC ACID INTERACTION

OBJECTIVE: To review information regarding the dual and interdependent drug-nutrient interaction between phenytoin and folic acid and other literature involving phenytoin and folic acid. DATA SOURCES: Informati on was retrieved from a MEDLINE search of English-language literature conducted from 1983 (time of the last review) to March 1995. Search te rms included folic acid, phenytoin, and folic acid deficiency. Additio nal references were obtained from Current Contents and from the biblio graphies of the retrieved references. STUDY SELECTION: All human studi es examining the effects of phenytoin on serum folate concentrations a nd folic acid supplementation on serum phenytoin concentrations were s elected. These included studies of patients with epilepsy and healthy volunteers as well as case reports. Case reports were included because of the extensive length of time needed to study this drug interaction . DATA EXTRACTION: Data extracted included gender, dosing, serum folat e concentrations if available, pharmacokinetics, and adverse events. D ATA SYNTHESIS: Serum folate decreases when phenytoin therapy is initia ted alone with no folate supplementation. Folic acid supplementation i n folate-deficient patients with epilepsy changes the pharmacokinetics of phenytoin, usually leading to lower serum phenytoin concentrations and possible seizure breakthrough. Folate is hypothesized to be a cof actor in phenytoin metabolism and may be responsible for the ''pseudo- steady-state,'' which is a concentration where phenytoin appears to be at steady-state, but in reality, is not. Phenytoin and folic acid the rapy initiated concomitantly prevents decreased folate and phenytoin o btains steady-state concentrations sooner. CONCLUSIONS: Folic acid sup plementation should be initiated each time phenytoin therapy commences because of the hypothesized cofactor mechanism, decreased adverse eff ects associated with folate deficiency, and better seizure control wit h no perturbation of phenytoin pharmacokinetics.