背景：Phenytoin 自1937 年上市以來常被使用於癲癇治療，但是phenytoin 無法由給藥劑量預期血中濃度，且血中濃度療效範圍狹窄，使用後必需作血中濃度監測。於穩定下，游離phenytoin 與總phenytoin 的比例約0.1，且總phenytoin 血中濃度檢測方法較為簡易，故phenytoin 一般是監測總phenytoin，但當重症病患病況不穩定時，游離phenytoin 與總phenytoin 的比例會改變，無法由總phenytoin 估計游離phenytoin 值，直接測定游離phenytoin 在臨床上因此有其價值。
方法：針對某一醫學中心神經內科加護病房監測總phenytoin 血中濃度者，自2009 年8 月起，增加檢驗游離phenytoin 項目，本研究中設立此項檢驗條件為具有腎功能不良且肌酐酸廓清率(Creatinine Clearance rate; CCr) 少於25 ml/min，或中度以上 (Child-Turcotte-Pugh B-C) 肝硬化，或併用valproic acid，凡具上述條件一項以上之病況不穩定病患，均加測游離phenytoin，資料收集至2010 年7 月31 日止。
結果：本研究分析共納入40 筆加測游離phenytoin 資料，結果顯示具腎功能失常(CCr < 25 ml/min) 或中度以上 (Child-Turcotte-Pugh B-C) 肝硬化，或併用valproic acid，凡具上述條件一項以上之病況不穩定病患，超過半數以上游離phenytoin 與總phenytoin 的比例有意義地改變，無法由總phenytoin 估計游離phenytoin。
結論：因重症病患常合併肝、腎功能不良、多重藥物交互作用或albumin 值偏低，影響phenytoin 蛋白結合率及代謝，對非線性排除的phenytoin，造成游離態與總量的比例改變，而利用Sheiner-Tozer公式估算游離phenytoin 的正確性受到條件限制，直接監測游離phenytoin 因此在臨床上作為phenytoin 劑量調整或考慮加入其他抗癲癇藥物以避免phenytoin 中毒上具有價值，但受限於游離phenytoin 檢驗價格貴及檢驗方法較耗時間，本研究可作為選擇病患監測游離phenytoin 的參考。
Background: Phenytoin has been widely used in epilepsy treatment since 1937. Due to the fact that the phenytoin serum concentration could not be extrapolated by the given doses and its characteristic of narrow therapeutic range, monitoring phenytoin serum concentration is necessary following treatment. In patients under clinically stable conditions, the serum phenytoin ratio of free form to total form (as a sum of bound plus free form) is about 0.1. Furthermore, monitoring total phenytoin concentration is practically simple. It is usually to monitor the total phenytoin concentration in clinical practice. Whilst the serum phenytoin ratio of free form to total form is altered in critically ill patients, the free phenytoin concentration can not be estimated from the total phenytoin concentration. Therefore, direct measurement of free phenytoin concentration has the clinical value.
Methods: This prospective study was carried out in a neurological intensive care unit of one medical center and the free phenytoin monitor was available since August 2009. In addition to monitor the total phenytoin concentration, free phenytoin concentration was performed if patients met any of the following criteria, renal insufficiency with creatinine clearance (CCr) less than 25 ml per minute, moderate to severe (Child-Turcotte-Pugh B-C) cirrhosis and concurrent use of valproic acid. Data were collected from August 2009 to July 31, 2010.
Results: 40 data were collected and revealed that more than half of the free form to total form ratio were significantly altered in clinically unstable patients with at least one of the aforementioned criteria. The free phenytoin concentration can not be estimated from the total phenytoin concentration in this population.
Conclusions: Phenytoin is nonlinear metabolized and highly protein binding. Critically ill patients were often associated with organ failure (e.g. liver or kidney dysfunction), multiple drug interactions and low serum albumin. All these factors can easily result in over-treatment due to the free form to total form ratio change and the clinical application of Sheiner-Tozer equation to estimate free phenytoin concentration is limitated. Direct monitoring of the free phenytoin is of clinically value in dose adjustments or appropriateness of adding other anticonvulsant to avoid phenytoin intoxication. This study provides practical considerations for the selection of patients to monitor the free phenytoin.
