Dingemanse J, van Bree J B, Danhof M
Division of Pharmacology, University of Leiden, The Netherlands.
J Pharmacol Exp Ther. 1989 May;249(2):601-8.
The aim of this study was to develop a model for the relationship between concentration and anticonvulsant effect of phenobarbital in the rat. The method of quantitating the anticonvulsant response on the basis of plasma pentylenetetrazol threshold concentrations, was optimized by application of a longitudinal study design. The pharmacokinetics of phenobarbital were studied in a separate set of rats (elimination half-life 11 +/- 2 hr). The anticonvulsant effect was measured 1 hr after i.v. administration. Concentration-effect relationships were assessed for serum (total and free), cerebrospinal fluid and brain concentrations on the basis of the sigmoid maximum effect model. The EC50 for total serum was 76 +/- 9 mg/l and for free serum, cerebrospinal fluid and brain 44 +/- 5, 43 +/- 7 and 50 +/- 8 mg/l and mg/kg, respectively (means +/- S.E.). The maximum effect was about 120 mg/l of pentylenetrazol. The respective EC50 ratios corresponded closely with the concentration ratios between the different compartments as determined by orthogonal regression analysis. For the greater part of the concentration range the concentration-effect relationship also could be fitted accurately to a simple linear model. Such relationships were not perturbed by the occurrence of seizures as these did not alter the distribution profile of phenobarbital. The pharmacokinetics and pharmacodynamics of p-hydroxyphenobarbital, the main metabolite of phenobarbital, also were investigated. This compound is eliminated very rapidly and has neither anticonvulsant activity of its own nor influences the anticonvulsant effect of phenobarbital at serum concentrations up to 30 mg/l. The described experimental strategies allow the study of factors influencing the concentration-anticonvulsant effect relationship of phenobarbital.
本研究的目的是建立一个关于苯巴比妥在大鼠体内浓度与抗惊厥作用之间关系的模型。通过应用纵向研究设计，优化了基于血浆戊四氮阈值浓度定量抗惊厥反应的方法。在另一组大鼠中研究了苯巴比妥的药代动力学（消除半衰期为11±2小时）。静脉注射1小时后测量抗惊厥作用。基于S形最大效应模型评估了血清（总血清和游离血清）、脑脊液和脑内浓度的浓度-效应关系。总血清的EC50为76±9mg/l，游离血清、脑脊液和脑内的EC50分别为44±5mg/l、43±7mg/l和50±8mg/kg（均值±标准误）。最大效应约为120mg/l的戊四氮。通过正交回归分析确定，各EC50比值与不同隔室之间的浓度比值密切相关。在大部分浓度范围内，浓度-效应关系也能准确地拟合为一个简单的线性模型。癫痫发作的发生并未干扰这种关系，因为癫痫发作并未改变苯巴比妥的分布情况。还研究了苯巴比妥的主要代谢产物对羟基苯巴比妥的药代动力学和药效学。该化合物消除非常迅速，自身没有抗惊厥活性，在血清浓度高达30mg/l时也不影响苯巴比妥的抗惊厥作用。所描述的实验策略有助于研究影响苯巴比妥浓度-抗惊厥作用关系的因素。
