Utilization of Km for Phenytoin Dosage after Folate Addition to Patient Regimen

Abstract

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.