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.


METHODS
Information was retrieved from a MEDLINE search of English-language literature conducted from 1983 (time of the last review) to March 1995. Search terms included folic acid, phenytoin, and folic acid deficiency. Additional references were obtained from Current Contents and from the bibliographies of the retrieved references.


METHODS
All human studies examining the effects of phenytoin on serum folate concentrations and folic acid supplementation on serum phenytoin concentrations were selected. 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.


METHODS
Data extracted included gender, dosing, serum folate concentrations if available, pharmacokinetics, and adverse events.


RESULTS
Serum folate decreases when phenytoin therapy is initiated alone with no folate supplementation. Folic acid supplementation in 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 cofactor 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 therapy initiated concomitantly prevents decreased folate and phenytoin obtains steady-state concentrations sooner.


CONCLUSIONS
Folic acid supplementation should be initiated each time phenytoin therapy commences because of the hypothesized cofactor mechanism, decreased adverse effects associated with folate deficiency, and better seizure control with no perturbation of phenytoin pharmacokinetics.
College of Pharmacy, University of Iowa, Iowa City 52242, USA.
D P
DP
Lewis
D C
DC
Van Dyke
L A
LA
Willhite
P J
PJ
Stumbo
M J
MJ
Berg
D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004827:Epilepsy / Q000188:drug therapy; D005492:Folic Acid / Q000494:pharmacology*; D005494:Folic Acid Deficiency / Q000188:drug therapy; D005527:Food, Fortified; D018565:Food-Drug Interactions; D006801:Humans; D010672:Phenytoin / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
D000927:Anticonvulsants; D010672:Phenytoin; D005492:Folic Acid