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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)

Folate was first isolated in an unknown form in 1941. The pharmaceutical form of folate is folic acid (pteroylglutamic acid). The major source of folate in the USA is food, with primary sources being grain products, especially fortified cereals, citrus fruits, and dried beans and lentils. However, the estimation of dietary intake of folate by food tables may not reflect actual intake because naturally occurring folate in the diet may be rendered inactive by cooking and food processing.

A patient with severe liver disease and mildly obnormal but stable renal function was given cimetidine on two occasions for gastrointestinal hemorrhage. In each course, dosing was initiated at half the recommended dosage of 600 mg daily, and mental status deteriorated shortly after dosing began. A further dosage decrease to 300 mg daily allowed continuation of cimetidine therapy in absence of mental status alterations. In this patient, mental status changes occurred at lower serum concentrations than we have previously reported. This discrepancy was explained by analysis of cimetidine CSF concentrations, as this patient had abnormally high cimetidine blood to CSF permeability. Although the cause of increased CSF concentrations is unclear, cimetidine-associated mental confusion was dose related and completely reversible upon a decrease in dosage. Patients who develop cimetidine-associated mental status changes and who cannot have treatment stopped may be safely treated by individualizing the dosing rate.

Summary: 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 (μg/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 μg/ml less and 5 μg/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 μg/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 μg/ml, for Km-1 and Km+5, respectively. The percentage increases in serum folate after taking FA while continuing PHT in Phase II were as follows: 38.78 ± 72.84%, Km-1 (1 mg FA): 81.38 ± 72.75%, Km+5 (1 mg FA); 138 ± 93.43%, Km-1 (5 mg FA); and 169.67 ± 69.67%, Km+5 (5 mg FA). Five milligrams FA increased the serum folate more than the 1-mg dose. The higher total PHT concentration was associated with a greater decrease in the serum folate. Therefore, serum folate may decrease early with PHT therapy and should be monitored at that time. RESUME Nous avons etudie l'effet de la phenytoine (PHT) sur les taux seriques de folates, et l'effet d'une supplementation orale d'acide folique (FA) sur les taux seriques de folates pendant le maintien de la PHT chez 13 volontaires sains de sexe masculin âges de 20 a 35 ans. L'etude s'est deroulee en deux temps: la phase la servi a determiner la Vmax (mg/kg/j/) et la Km (μg/ml) de PHT pour calculer les doses de PHT necessaires a la phase II. La phase II est une etude croisee a quatre voies visant a determiner l'effet de I et 5 mg de FA sur les concentrations seriques de PHT inferieures de 1 μg/ml et superieures de 5 μg/ml au Km, Km-1 et Km+5, respectivement, chez chaque sujet. L'effet de la PHT sur les taux sanguins de FA a eteetudiee pendant toutes les phases de l'etude. Pendant la phase I, les taux de FA ont diminue de42.15 ± 21.44% (moyenne ± DS) apres 24.15 ± 5.63 jours de traitement par PHT, avec une concentration moyenne de PHT serique totale en phase stable de 8.45 ± 2.70 μg/ml. En phase II, le pourcentage moyen de diminution du taux de FA avant supplementation de 1 et 5 mg etait pour Km - 1 et Km + 5 respectivement de 12.80 ± 31.45% et de 23.24 ± 21.24%. Avant supplementation en FA. pour Km - 1 et Km + 5, la duree moyenne de l'administration de PHT etait de 9.52 ± 3.34 et de 15.84 ± 7.02 jours, et la concentration serique totale de PHT de 2.60 ± 2.18 et 8.64 ± 3.34 μg/ml respectivement. Le pourcentage d'augmentation des folates seriques apres supplementation en FA et maintien de la PHT en phase II etait le suivant: 38.78 ± 72.84%, Km - 1 (1 mg FA); 81.38 ± 72.75%, Km + 5 (1 mg FA); 138. ± 93.43%, Km - 1 (5 mg FA); 169.67 ± 69.67%, Km + 5 (5 mg FA). L'administration de 5 mg FA a entraine une augmentation des folates sanguins superieure a celle obtenue apres 1 mg FA. Les concentration elevees de PHT ont entrainea des diminutions plus importantes des folates sanguins. Les folates sanguins peuvent ectre abaisses precocement par le traitement par PHT, et doivent etre surveilles des l'instauration d'un tel traitement. RESUMEN En 13 sujetos varones de 20 a 35 anos de edad sin ningun tipo de enfermedad, se han estudiado los efectos de la fenitoina (PHT) sobre el folato serico y los efectos de la administracion adicional de acido folico por via oral (FA) sobre el folato serico mientras se continuaba tomando la PHT. Este estudio se ha dividido en dos fases: la Fase I determineo la Vmax (mg/Kg/d/ia) y la Km (μg/ml) de la PHT para calcular las dosis de PHT necesarias para la segunda fase. La Fase II consistio en un estudio cruzado de 4 dias para examinar el efecto de I y 5 mg de FA sobre las concentraciones sericas de FTA de menos de 1 μg/ml y mayores de 5 μg/ml que los sujetos Km, Km - 1 y Km + 5, respectivamente. Ambas fases examinaron los efectos de la PHT sobre el folato serico. En la Fase I el folato serico se redujo en un promedio y desviacion tipica de 42.15 ± 21.44% despues de un promedio de 24.15 ± 5.63 dias de administracion de la PHT con un promedio de situacion estable de concentraciones sericas de PHT de 8.45 ± 2.70 μg/ml. La reduccion media del porcen-taje del folato serico antes de la adicion de 1 y 5 mg de FA en la Fase II fue de 12.80 ± 31.45% y 23.24 ± 21.24% para los Km - 1 y Km + 5, respectivamente. El promedio del numero de dias de administracion de la PHT y de las concentraciones sericas de PHT antes de la administracion de FA fue de 9.52 ± 3.34 dias y 15.84 ± 7.02 dias y 2.60 ± 2.18 μg/ml y 8.64 ± 3.44 μg/ml para los Km - 1 y Km + 5 respectivamente. El incremento del porcentaje de folato serico despues de tomar el FA mientras se continuaba con la PHT en la Fase II, fue el siguiente: 38.78 ± 72.84%, en los Km - 1 (1 mgde FA); 81.38 ± 72.75% en ios Km + 5 (1 mg de FA); 138 ± 93.43% en los Km - 1 (5 mg de FA) y 169.67 ± 69.67 en los Km + 5 (5 mg de FA). Los 5 mg de FA incrementaron el folato serico mas que la dosis de lmg. Las concentraciones totales mas altas de PHT se asociaron a una reduccion mas intensa del folato serico. Por estas razones se deduce que el folato serico puede reducirse precozmente con la terapia de PHT y debe ser monitorizado en este momento. ZUSAMMENFASSUNG Der Einflus von Phenytoin (PHT) auf Serum-Folsaure und der Einflus von oraler Folsauregabe (FA) auf Serum-Folsaure unter PHT-Medikation wurde an 13 gesunden Mannern zwischen 20 und 35 Jahren untersucht. Die Studie wurde in zwei Phasen unterteilt; In Phase I wurde Vmax (mg/kg/d/) und Km (μ/ml) von PHT bestimmt, um die PHT-Dosen fur die zweite Phase zu ermitteln. Phase II war eine 4-Wege-Crossover-Studie um den Effekt von 1 und 5 mg FS auf PHT-Konzentration 1 μg/ml kleiner und 5 μg/ml groser als die jeweiligen Km, Km - 1 und Km + 5 der Patienten zu untersuchen. In beiden Phasen wurde der Einflus von PHT auf Serum-Folsaure untersucht. In Phase I sank Serum-Folsaure um einen Durchschnitt und eine Standar-dabweichung von 42.15 ± 21.44% nach durchschnittlich 24.15 ± 5.63 Tagen von PHT-Gabe mit einem durchschnittlichen PHT-Spiegel von 8.45 ± 2.70 μg/ml. Die durchschnittliche prozentuale Erniedrigung der Serum-Folsaure betrug vor der zusatzlichen Gabe von 1 und 5 mg FA in Phase II 12.80 ± 31.45% und 23.24 ± 21.24% fur jeweils Km - 1 und Km + 5. Die durchschnittliche Anzahl von Tagen unter PHT-Medikation und die PHT-Serum-Konzentrationen vor FA-Gabe war 9.52 ± 3.34 Tage und 15.84 ± 7.02 Tage und 2.60 ± 2.18 μg/ml und 8.64 ± 3.44 μg/ml fur jeweils Km - 1 und Km + 5. Der durchschnittliche Anstieg der Serum-Folsaure nach Einnahme von FA unter Fortfuhrung der PHT-Gabe in Phase II war folgender; 38.78 ± 72.84%, Km - 1 (1 mg FA); 81.38 ± 72.75%, Km + 5(1 mg FA) 138 ± 93.43%, Km - 1 (5 mg FA) und 169.67 ± 69.67, Km + 5 (5 mg FA). 5 mg FA erhohte die Serum-Folsaure starker als die 1 mg-Dosis. Eine hohere PHT-Konzentration war assoziiert mit einem groseren Abfall der Serum-Folsaure. Daraus folgt, das Serum-Folsaure-Werte eventuell schon zu Beginn einer PHT-Therapie erniedrigt werden und deshalb zu diesem Zeitpunkt uberwacht werden sollten.