The relationship between the pharmacological effect of amitriptyline based on an improved forced-swimming test and plasma concentration in rats.

Abstract

The relationship between the plasma concentration of amitriptyline (AMI) and its pharmacological effect was investigated in rats. The plasma concentration of AMI was maintained constantly from 5 h to 7 d after intraperitoneal infusion by the implantation of an osmotic minipump with an adjusted release rate of 20 mg/kg/d of AMI. Neither the plasma or brain concentrations of AMI in a 24-h infusion group were significantly different as compared with those in the 7-d group. The pharmacological effect of AMI was measured by our improved forced-swimming test. When AMI (dose of 20 and 50 mg/kg/d) was infused, the pharmacological effect in both infusion groups of rats was increased significantly at each dose in comparison to that of the control rats (p < 0.05). With 10 mg/kg/d infusion, the effect in the 7-d group increased significantly as compared with that of the control (p < 0.05), although the effect in the 24-h group did not change. The effect was increased in both groups with an increase of dose. When the effect was plotted to the area under the plasma concentration-time curve (AUC), the effect approached a limiting value (12 micrograms/ml.h). Therefore, it was suggested that 12 micrograms.ml/h as the AUC for AMI was enough to obtain a maximum AMI pharmacological effect in rats. From these results, we concluded that the AUC for AMI may be a useful index to evaluate its pharmacological effect, rather than the plasma concentration.