Leppik I E, Boucher R, Wilder B J, Murthy V S, Rask C A, Watridge C, Graves N M, Rangel R J, Turlapaty P
Department of Neurology, University of Minnesota, Minneapolis.
Epilepsia. 1989;30 Suppl 2:S22-6. doi: 10.1111/j.1528-1157.1989.tb05821.x.
The currently available phenytoin (PHT) solution has many disadvantages stemming from poor aqueous solubility of PHT. A novel approach to solve the problem has been the synthesis of a phosphate ester of PHT (PHT prodrug ACC-9653). This water-soluble compound is metabolized rapidly into PO4 and PHT. A four center open-label, baseline-controlled study of 43 patients with epilepsy maintained on oral twice-daily PHT monotherapy was performed to evaluate the safety and pharmacokinetic profile of the prodrug. Patients received an i.v. or i.m. dose of ACC-9653 at a dose equivalent to the patients' morning dose of PHT. Intravenous dosages were infused at a rate of 75 mg/min, and i.m. dosages were given as one or two injections. After a period of 6 days, during which patients were again maintained with oral PHT, they were given a dose of ACC-9653 via whichever route they had not yet received. The Tmax of the prodrug averaged 5.7 and 36 min (0.095 and 0.606 h) after i.v. and i.m. administrations, respectively. The elimination half-life of ACC-9653 (conversion from prodrug to PHT) after i.v. and i.m. administration was 8.4 and 32.7 min (0.140 and 0.545 h), respectively, and both were independent of the dose. The plasma clearance of ACC-9653 was not dependent on dose or route of administration and averaged 19.8 +/- 1.16 and 17.8 +/- 0.83 L/h after i.v. and i.m. administrations, respectively. The area under curve ratio of PHT after i.m. and i.v. ACC-9653 was 1.17 +/- 0.13 which was not significantly different from 1.(ABSTRACT TRUNCATED AT 250 WORDS)
目前可用的苯妥英（PHT）溶液存在许多缺点，这些缺点源于PHT的水溶性较差。解决该问题的一种新方法是合成PHT的磷酸酯（PHT前药ACC - 9653）。这种水溶性化合物会迅速代谢为磷酸根和PHT。进行了一项针对43例癫痫患者的四中心开放标签、基线对照研究，这些患者维持每日两次口服PHT单药治疗，以评估该前药的安全性和药代动力学特征。患者接受静脉注射或肌肉注射相当于其早晨PHT剂量的ACC - 9653。静脉注射剂量以75毫克/分钟的速度输注，肌肉注射剂量分一次或两次注射。在6天期间，患者再次维持口服PHT，之后通过他们尚未接受的任何一种途径给予一剂ACC - 9653。前药的达峰时间在静脉注射和肌肉注射后平均分别为5.7分钟和36分钟（0.095小时和0.606小时）。静脉注射和肌肉注射后ACC - 9653（从前药转化为PHT）的消除半衰期分别为8.4分钟和32.7分钟（0.140小时和0.545小时），且两者均与剂量无关。ACC - 9653的血浆清除率不依赖于剂量或给药途径，静脉注射和肌肉注射后平均分别为19.8±1.16升/小时和17.8±0.83升/小时。肌肉注射和静脉注射ACC - 9653后PHT的曲线下面积比为1.17±0.13，与1无显著差异。（摘要截断于250字）
