てんかん患者におけるPhenytoin吸収の問題点 : 剤形による吸収率の変化とその薬物速度論

概要

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The unpredictable fluctuations in plasma levels (Cp) of phenytoin (PHT) were observed in three impatients who received PHT powders from the same lot (PHT (P)). All three patients had organic brain disorders (cerebral infarction, severe mental retardation, porencephaly). One patient with mental retardation was a 5-year-old girl and the other patients were elderly men in poor physical condition. The fluctuations mentioned above were reduced in size after a change in drug prepartion and Cp was stabilized by the use of PHT granules (PHT (G)) or PHT tablets (PHT (T)). Through serial intensive monitoring, it was revealed pharmacokinetically that the absorption rate (F) of PHT (P) fluctuated between 0.54 and 0.90; otherwise, F of PHT (G) and PHT (T) stabilized at 0.95 and 0.80, respectively. The pharamcokinetic calculations were based on the assumption that the absorption rate constants (Ka) were 0.2 hr-1 for PHT (P), 0.5 hr-1 for PHT (G) and 0.3 hr-1 for PHT (T) and distribution volume (Vd) of PHT was 1.0 liter/kg. The fluctuations of Cp were explained most reasonably by the changes of F of PHT (P) in all three cases. This was well documented in one patient with a low Michaelis-Menten constant (KM=1.25μg/ml). Our study emphasizes that intensive monitoring and the use of preparations with stable F are very important for therapeutic use of PHT, because PHT is a drug that shows saturation kinetics under the therapeutic situations.