Leppik I E, Sherwin A L
Epilepsia. 1979 Jun;20(3):201-7. doi: 10.1111/j.1528-1157.1979.tb04796.x.
14C-phenytoin or 3H-phenobarbital were given through indwelling jugular catheters to 65 rats. Anticonvulsant activity was tested by the maximal electroshock seizure test and was correlated with brain concentrations of phenytoin or phenobarbital. Free and total plasma drug levels were determined by equilibrium dialysis. The median effective cerebral phenytoin concentration (EC50) was 10.5 microM/kg (95% fiducial limits, 8.2 to 12.4) 3 min after infusion compared with 10.2 microM/kg 30 min after infusion. The EC50 of phenobarbital was 8.2 microM/kg (6.7 to 9.3 microM/kg) 3 min after infusion. Cerebellar concentrations were equivalent to cerebral concentrations for all rats (r = 0.98). Three minutes after infusion, cerebral:plasma free ratio of phenytoin was 3.73 +/- 0.71 (+/- S.D.); the plasma protein bound:free ratio, 3.70 +/- 0.98. For phenobarbital, the cerebral:plasma free ratio was 0.72 +/- 0.10; the plasma protein bound:free ratio, 0.63 +/- 0.12. Since the EC50 values of phenytoin 3 or 30 min after infusion did not differ, onset of anticonvulsant effect clearly occurred as soon as adequate brain concentrations were attained. Phenobarbital was effective 3 min after infusion, and although much higher free plasma levels were necessary, effective brain concentrations were similar to those of phenytoin. Brain content paralleled plasma protein binding, both being high for phenytoin and low for phenobarbital.
通过颈静脉留置导管给65只大鼠注射14C - 苯妥英或3H - 苯巴比妥。通过最大电休克惊厥试验测试抗惊厥活性，并将其与苯妥英或苯巴比妥的脑浓度相关联。通过平衡透析测定游离和总血浆药物水平。输注后3分钟，苯妥英的中位有效脑浓度（EC50）为10.5微摩尔/千克（95%置信限，8.2至12.4），而输注后30分钟为10.2微摩尔/千克。苯巴比妥的EC50在输注后3分钟为8.2微摩尔/千克（6.7至9.3微摩尔/千克）。所有大鼠的小脑浓度与脑浓度相当（r = 0.98）。输注后3分钟，苯妥英的脑：血浆游离比率为3.73±0.71（±标准差）；血浆蛋白结合：游离比率为3.70±0.98。对于苯巴比妥，脑：血浆游离比率为0.72±0.10；血浆蛋白结合：游离比率为0.63±0.12。由于输注后3分钟或30分钟苯妥英的EC50值没有差异，抗惊厥作用显然在达到足够的脑浓度后立即出现。苯巴比妥在输注后3分钟有效，虽然需要更高的游离血浆水平，但有效的脑浓度与苯妥英相似。脑含量与血浆蛋白结合平行，苯妥英两者都高，苯巴比妥两者都低。
