Department of Pharmacology, Material Medica and Therapeutics, University of Manchester.
Br J Clin Pharmacol. 1974 Apr;1(2):163-8. doi: 10.1111/j.1365-2125.1974.tb00226.x.
1 A preliminary survey showed that many outpatients with partially controlled epilepsy had serum concentrations of phenytoin below the recommended therapeutic range (10-20 μg/ml). A phenytoin tolerance test was devised with the intention of predicting a more adequate daily dose for such a patient. 2 Fifteen patients were each given an oral test dose of 600 mg phenytoin sodium and the serum concentration of phenytoin was measured at intervals over 48 h; the concentration rose during the first 4 h and decayed between 12-48 h as an almost linear function of time. 3 The serum concentration/time curves were fitted by an interative computer program based on the Michaelis-Menten equation. The mean saturated rate of elimination of phenytoin was 435 mg/day and the serum concentration (K(m)) corresponding with 50% saturation was 3.8 μg/ml. The mean calculated dose of phenytoin sodium required for a steady state serum concentration of 10-20 μg/ml was 345-400 mg/day. 4 The Michaelis-Menten principle was used to predict steady state serum phenytoin concentrations in individual patients receiving daily doses of phenytoin sodium adjusted by steps of 100 mg. The serum concentrations tended to be either too low or too high. The steep relationship between phenytoin concentration and dose indicates that when the concentration reaches 5-10 μg/ml it is then appropriate to adjust dose by small steps of about 25 mg.
初步调查显示，许多部分控制的癫痫患者的血清苯妥英钠浓度低于推荐的治疗范围（10-20μg/ml）。设计了苯妥英钠耐受试验，旨在预测此类患者更合适的日剂量。
15 名患者每人给予 600mg 苯妥英钠钠的口服试验剂量，并在 48 小时内每隔一段时间测量血清苯妥英钠浓度；浓度在前 4 小时内上升，在 12-48 小时之间以时间的几乎线性函数下降。
血清浓度/时间曲线通过基于米氏方程的迭代计算机程序拟合。苯妥英钠的平均饱和消除率为 435mg/天，对应 50%饱和的血清浓度（K(m)）为 3.8μg/ml。达到 10-20μg/ml 稳态血清浓度所需的苯妥英钠钠的平均计算剂量为 345-400mg/天。
米氏原理用于预测每天接受苯妥英钠钠剂量调整 100mg 步长的个体患者的稳态血清苯妥英浓度。血清浓度往往过低或过高。苯妥英钠浓度与剂量之间的陡峭关系表明，当浓度达到 5-10μg/ml 时，通过约 25mg 的小步调整剂量是合适的。
