Brain concentrations of tricyclic antidepressants: single-dose kinetics and relationship to plasma concentrations in chronically dosed rats.

A previously reported method of measuring tricyclic antidepressant concentrations in brain tissue and plasma was used to measure amitriptyline (AMI) in rats following drug administration using different routes, doses, and time intervals. In rats given AMI intraperitoneally (IP), brain concentrations increased during the first 30 min after drug administration and then declined. Brain concentrations increased linearly with changes in IP dosage and increased logarithmically with changes in intravenous dosage. No simple relationship existed between brain and plasma concentrations in acutely dosed rats. However, a linear relationship existed between plasma and brain concentrations in chronically treated animals (r = 0.96, P less than 0.001). The brain:plasma drug ratios observed in chronically treated rats corresponded to ratios reported in man. Thus, conclusions drawn from these studies can probably be extrapolated to the clinical situation. Based on our data, the molar concentration of drug achieved on therapeutic doses is 10(-5)--10(-6) M. This information may aid in understanding the clinical relevance of in vitro drug: receptor binding studies which are typically reported in molar concentrations.