Phenytoin Pharmacokinetics: Before and After Folic Acid Administration

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Abstract
Phenytoin (PHT) exhibits linear and Michaelis-Menten pharmacokinetics. PHT decreases serum folate; the vitamin folic acid (FA) is hypothesized to be a cofactor in the metabolism of PHT. The depletion of serum folate may explain the unpredictability of measured total serum PHT concentrations and time to steady state as compared with the Michaelis-Menten predictive calculations. We examined PHT pharmacokinetics before and after FA supplementation in 13 healthy male volunteers. The study was divided into two phases. Phase I determined V(max) (mg/day) and Km (micrograms/ml) of PHT to calculate PHT doses needed for the second phase. Phase II was a four-way cross-over study to examine the effect of 1 and 5 mg FA on total serum PHT concentrations 1 microgram/ml less and 5 micrograms/ml greater than the subject's Km, Km - 1 and Km + 5, respectively. Predicted versus measured total serum PHT concentrations, t90% (days to steady state), and the effect of FA were calculated for Km - 1 and Km + 5 before and after 1 or 5 mg FA. The measured total serum PHT concentration was always greater than the calculated concentration (p less than 0.05), and t90% was always longer than the calculated t90% (p less than 0.05) for Km - 1 before FA (all subjects decreased serum FA); the same was observed for Km + 5. If folate is assumed to be a cofactor in PHT metabolism, these results are expected, because depletion of the vitamin would indicate less folate to drive the metabolism of PHT, resulting in higher total serum PHT concentrations and longer time to reach steady state.(ABSTRACT TRUNCATED AT 250 WORDS)