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 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)

Decrease of serum folates in healthy male volunteers taking phenytoin.

The effect of phenytoin (PHT) on serum folate and the effect of additional oral folic acid (FA) on serum folate during continued treatment with PHT were studied in 13 healthy male subjects 20-35 years of age. The study was divided into two phases: Phase I determined Vmax (mg/kg/day) and Km (microgram/ml) of PHT in order to calculate the 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. Both phases examined the effect of PHT on serum folate. In Phase I, serum folate decreased by a mean and standard deviation of 42.15 +/- 21.44% after an average of 24.15 +/- 5.63 days of PHT administration, with a mean steady-state total serum PHT concentration of 8.45 +/- 2.70 micrograms/ml. Mean percentage decreases in serum folate before the addition of 1 and 5 mg FA in Phase II were 12.80 +/- 31.45% and 23.24 +/- 21.24% for Km-1 and Km+5, respectively. The average numbers of days of PHT administration and total serum PHT concentrations before FA administration were 9.52 +/- 3.34 and 15.84 +/- 7.02 days, and 2.60 +/- 2.18 and 8.64 +/- 3.44 micrograms/ml, for Km-1 and Km+5, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Phenytoin binding in healthy volunteers.

The pharmacologic effect of phenytoin is directly related to the unbound concentration in the serum, which previously has been reported in the literature to be approximately 10%. The results of 13 out of 14 20-35 year-old healthy male volunteers studied indicate that less than 10% unbound phenytoin is present in the majority of subjects taking two different doses of phenytoin.

Utilization of Km for phenytoin dosage after folate addition to patient regimen.

Phenytoin decreases serum and red blood cell folates in 50% of the patients on the anticonvulsant. The supplementation of folic acid changes the disposition of phenytoin, a drug that exhibits Michaelis-Menten kinetics. In a retrospective study at the Veterans Administration Medical Center, seven adult male folate-deficient epileptic patients on phenytoin alone and compliant with the anticonvulsant were supplemented with 1 mg oral folic acid. Before and after the addition of the vitamin, Vmax and Km were calculated for phenytoin. With folic acid, the total serum phenytoin concentration decreased significantly by an average of 22.6 +/- 13.0%. The Km decreased significantly from 6.7 +/- 1.1 to 4.1 +/- 1.5 micrograms/ml. The Vmax remained unchanged. It is hypothesized that folic acid is a cofactor in the metabolism of phenytoin. A cofactor would be expected to alter the affinity (Km) of the enzymes for phenytoin with no change in the liver's total capacity (Vmax) to metabolize phenytoin. This retrospective study in seven male epileptic patients is a convincing argument for the hypothesis.