Perucca E, Hebdige S, Frigo G M, Gatti G, Lecchini S, Crema A
Clin Pharmacol Ther. 1980 Dec;28(6):779-89. doi: 10.1038/clpt.1980.235.
The effect of sodium valproate (400 mg three times daily) on the disposition kinetics of intravenous phenytoin (250 mg) was investigated in seven normal subjects. After valproate, the free (unbound) fraction of phenytoin in serum rose from 9.6 +/- 0.9% (SD) to 15.6 +/- 1.4% on average (p < 0.001). The effect was associated with an increase in systemic clearance and apparent volume of distribution of total drug. There was a strong positive correlation between percent increment in each of these parameters and percent increment in unbound drug in serum. Free phenytoin concentration in serum and phenytoin concentration in saliva increased during valproate administration. As a result, both the clearance and the apparent volume of distribution of free drug were reduced. There was an increase in the renal excretion of unchanged phenytoin during valproate administration, but the effect was too small to have an appreciable influence on the overall clearance of the drug. There were no consistent changes in the excretion of the major metabolite 5, p-hydroxyphenyl, 5-phenyl, hydantoin (pHPPH), in the urine. These results suggest that valproic acid may have two separate and opposing effects on phenytoin disposition: (1) displacing phenytoin from plasma protein binding sites, thereby enhancing the systemic clearance of total drug, and (2) inhibiting phenytoin metabolism, thereby increasing the concentration of free drug in the serum.
在7名正常受试者中研究了丙戊酸钠（每日3次，每次400毫克）对静脉注射苯妥英钠（250毫克）处置动力学的影响。服用丙戊酸钠后，血清中苯妥英钠的游离（未结合）分数平均从9.6±0.9%（标准差）升至15.6±1.4%（p<0.001）。该效应与总药物的全身清除率增加和表观分布容积增加有关。这些参数中每一个的增加百分比与血清中游离药物的增加百分比之间存在强正相关。在服用丙戊酸钠期间，血清中游离苯妥英钠浓度和唾液中苯妥英钠浓度升高。结果，游离药物的清除率和表观分布容积均降低。服用丙戊酸钠期间苯妥英钠原形的肾排泄增加，但该效应太小，对药物的总体清除率没有明显影响。尿液中主要代谢产物5-对羟基苯基-5-苯基乙内酰脲（pHPPH）的排泄没有一致变化。这些结果表明，丙戊酸可能对苯妥英钠的处置有两种独立且相反的作用：（1）将苯妥英钠从血浆蛋白结合位点置换出来，从而提高总药物的全身清除率；（2）抑制苯妥英钠代谢，从而增加血清中游离药物的浓度。
