PHENYTOIN PHARMACOKINETICS - BEFORE AND AFTER FOLIC-ACID ADMINISTRATION

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 K(m) (mu-g/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-mu-g/ml less and 5-mu-g/ml greater than the subject's K(m), K(m-1) and K(m+5), respectively. Predicted versus measured total serum PHT concentrations, t90% (days to steady state), and the effect of FA were calculated for K(m-1) and K(m+5) before and after 1 or 5 mg FA. The measured total serum PHT concentration was always greater than the calculated concentration (p < 0.05), and t90% was always longer than the calculated t90% (p < 0.05) for K(m-1), before FA (all subjects decreased serum FA); the same was observed for K(m+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. Even though steady-state criterion was satisfied, "pseudo-steady state" could have occurred, making the time to steady state longer and possibly increasing total serum PHT further. When FA was added, the same results were obtained. Neither was there any difference in total serum PHT concentration before and after either 1 or 5 mg FA. These latter results may be explained by the fact that depletion of FA had to be corrected first before the role of FA as a cofactor in PHT metabolism could be used. Therefore, the interdependence of PHT and FA may explain the pseudo-steady state observed for PHT and the deviations from the Michaelis-Menten predictive calculations. Perhaps FA supplementation should be recommended when PHT therapy is initiated.