Stijnen A M, Hovinga S, Langemeijer M W, Hoogerkamp A, van Bezooijen C F, Danhof M
Center for Bio-Pharmaceutical Sciences, University of Leiden, The Netherlands.
Pharm Res. 1993 Jul;10(7):1046-51. doi: 10.1023/a:1018975025417.
The aim of the present investigations was to study the influence of increasing age on the pharmacodynamics of valproate in BN/BiRij rats, applying a threshold for electrically induced localized seizure activity as a measure of the anticonvulsant effect. Seven groups of healthy male BN/BiRij rats were used, aged 3, 6, 12, 19, 25, 31, and 37 months. Individual plasma concentration versus anticonvulsant effect relationships were determined during a continuous intravenous infusion of sodium valproate at a rate of 5.5 mg/min/kg. The infusion was terminated when the anticonvulsant effect intensity had reached the maximum attainable level or at a total infusion time of three hours. A nonlinear relationship between valproate concentration and anticonvulsant effect intensity was observed with no maximal effect in the concentration range up to 1200 mg.L-1. With increasing age a parallel shift in the concentration versus anticonvulsant effect relationships toward lower concentrations occurred. Thus increasing age appears to be associated with an increased sensitivity to the anticonvulsant effect of valproate.
本研究的目的是研究年龄增长对丙戊酸盐在BN/BiRij大鼠体内药效学的影响，采用电诱导局部癫痫发作活动的阈值作为抗惊厥作用的衡量指标。使用了七组健康雄性BN/BiRij大鼠，年龄分别为3、6、12、19、25、31和37个月。在以5.5mg/min/kg的速率持续静脉输注丙戊酸钠期间，确定了个体血浆浓度与抗惊厥作用的关系。当抗惊厥作用强度达到最大可达到水平或总输注时间为三小时时，终止输注。观察到丙戊酸盐浓度与抗惊厥作用强度之间存在非线性关系，在高达1200mg.L-1的浓度范围内没有最大效应。随着年龄的增加，浓度与抗惊厥作用关系向较低浓度平行移动。因此，年龄增长似乎与对丙戊酸盐抗惊厥作用的敏感性增加有关。
