Hatanaka T, Negishi S, Katayama K, Kakemi M, Koizumi T
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Japan.
J Pharmacobiodyn. 1988 Jan;11(1):47-52. doi: 10.1248/bpb1978.11.47.
The effect of chlorpromazine on the duration of loss of righting reflex (LRR, sleeping time) of pentobarbital and vice versa in a various dosage ranges were studied in rats. The logarithm of the dose versus sleeping time profile of pentobarbital was shifted to the left and the slope of the profile was decreased as the dose of chlorpromazine was increased. The logarithm of chlorpromazine dose versus duration of LRR during pentobarbital coadministration also showed a distinct dose-dependent profile. However, chlorpromazine itself showed ambiguous duration of LRR because the terminal point of the pharmacologic effect, i.e., the recovery of the righting reflex (RRR, the awakening time), was often difficult to determine clearly. The isobolographic method was introduced to describe the drug interaction of pentobarbital and chlorpromazine quantitatively. Assuming that the sites of action of chlorpromazine and pentobarbital were in the brain, the brain concentrations of pentobarbital at RRR were plotted against the brain concentration of chlorpromazine at RRR. The plots showed a hyperbola-like curve, indicating that there was a supra-additive interaction. In order to clarify the relationship between brain concentrations of the two drugs at RRR, a theoretical consideration was made under the following assumptions: (1) chlorpromazine and pentobarbital have a common central depressant effect, (2) the concentration-effect relationship is described by Hill's equation and (3) the mode of interaction of these drugs is simple additive. The results indicated that the isobolographic plot of pentobarbital and chlorpromazine was reasonably described by the theory and that chlorpromazine enhanced the effect of pentobarbital at least in an additive manner.
在大鼠中研究了氯丙嗪在不同剂量范围内对戊巴比妥致翻正反射消失持续时间（LRR，睡眠时间）的影响，以及戊巴比妥对氯丙嗪的影响。随着氯丙嗪剂量增加，戊巴比妥剂量与睡眠时间曲线的对数向左移动，曲线斜率降低。氯丙嗪剂量与戊巴比妥合用时LRR持续时间的对数也呈现出明显的剂量依赖性曲线。然而，氯丙嗪本身的LRR持续时间不明确，因为药理效应的终点，即翻正反射恢复（RRR，苏醒时间），常常难以清晰确定。引入等效应线法来定量描述戊巴比妥和氯丙嗪的药物相互作用。假设氯丙嗪和戊巴比妥的作用部位在脑内，将RRR时戊巴比妥的脑浓度与RRR时氯丙嗪的脑浓度绘制成图。这些图呈现出双曲线样曲线，表明存在超相加相互作用。为了阐明RRR时两种药物脑浓度之间的关系，在以下假设下进行了理论考量：（1）氯丙嗪和戊巴比妥具有共同的中枢抑制作用，（2）浓度-效应关系用希尔方程描述，（3）这些药物的相互作用模式为简单相加。结果表明，该理论合理地描述了戊巴比妥和氯丙嗪的等效应线图，且氯丙嗪至少以相加方式增强了戊巴比妥的作用。
