Steady-state plasma levels during antidepressant therapy with amitriptyline and amitriptylinoxide.

Plasma levels of amitriptyline, amitrypylinoxide, and their metabolites were analyzed in a controlled clinical trial with two groups of depressed patients. After administration of both drugs, demethylated and hydroxylated derivatives proved to be the main metabolites, and to a great extent amitriptylinoxide was reduced to amitriptyline. Continuous oral application of 150 mg/os per day of each drug resulted in therapeutically effective concentrations in both groups; however, concentrations were two to three times higher in the group receiving amitriptyline, rather than amitriptylinoxide. Based on the steady-state plasma levels, the total clearance of amitriptyline was calculated with a magnitude of 7 ml/min per kg. A first-order kinetic model was proposed to estimate the steady-state concentrations of consecutive metabolites, employing available kinetic data. Computed levels of nortriptyline after application of amitriptyline and amitriptylinoxide were 61.1 and 20.3 ng/ml, respectively, compared to nortriptyline levels determined with HPLC, which were 70.1 and 26.5 ng/ml, respectively. The model is discussed in relation to its practical use during monitoring of drug therapy with tricylics.