Jamerson B D, Donn K H, Dukes G E, Messenheimer J A, Brouwer K L, Powell J R
School of Pharmacy, University of North Carolina, Chapel Hill.
Epilepsia. 1990 Sep-Oct;31(5):592-7. doi: 10.1111/j.1528-1157.1990.tb06111.x.
3-Phosphoryloxymethyl phenytoin disodium (ACC-9653) is a water-soluble investigational phenytoin (PHT) prodrug for parenteral administration. The objectives of this investigation were to determine the absolute bioavailability and free fraction of PHT after intravenous (i.v.) administration of ACC-9653. Twelve healthy male volunteers received PHT sodium (250 mg/5 ml; 229.95 mg free acid) and ACC-9653 (375 mg/5 ml; 232.87 mg free acid) i.v. in 30 min in a randomized, double-blind cross-over fashion. The conversion half-life (t 1/2) of ACC-9653 to PHT was 9.3 +/- 2.7 min. ACC-9653 was not detected in urine and greater than 99% of ACC-9653 was converted to PHT. The PHT area under the curve (AUC) was not statistically different between treatments; the bioavailability of PHT after ACC-9653 was 99 +/- 11%. The fraction of unbound converted PHT at the end of the prodrug infusion, in the presence of 44 micrograms/ml ACC-9653, was significantly higher than at 180 min, when the concentration of ACC-9653 was 0.1 microgram/ml. ACC-9653 was shown to be a bioequivalent PHT prodrug exhibiting less irritation at the injection site than the current marketed PHT.
3-磷酸氧甲基苯妥英二钠（ACC - 9653）是一种用于肠胃外给药的水溶性苯妥英（PHT）前体药物。本研究的目的是确定静脉注射ACC - 9653后PHT的绝对生物利用度和游离分数。12名健康男性志愿者以随机、双盲交叉方式在30分钟内静脉注射苯妥英钠（250 mg/5 ml；229.95 mg游离酸）和ACC - 9653（375 mg/5 ml；232.87 mg游离酸）。ACC - 9653转化为PHT的半衰期（t1/2）为9.3±2.7分钟。尿液中未检测到ACC - 9653，超过99%的ACC - 9653转化为PHT。各治疗组之间PHT的曲线下面积（AUC）无统计学差异；ACC - 9653给药后PHT的生物利用度为99±11%。在存在44微克/毫升ACC - 9653的情况下，在前体药物输注结束时未结合的转化PHT分数显著高于180分钟时，此时ACC - 9653的浓度为0.1微克/毫升。结果表明，ACC - 9653是一种生物等效的PHT前体药物，在注射部位引起的刺激比目前市售的PHT小。
