STEADY-STATE KINETICS OF FLUOXETINE AND AMITRIPTYLINE IN PATIENTS TREATED WITH A COMBINATION OF THESE DRUGS AS COMPARED WITH THOSE TREATED WITH AMITRIPTYLINE ALONE

The steady-state kinetics of amitriptyline (AMI), fluoxetine (FLU), an d their active metabolites nortriptyline (NTRIP) and norfluoxetine (NF LU) were studied in 15 patients treated once daily for long durations with 50 mg of AMI and 20 mg of FLU. These compounds were analyzed simu ltaneously in plasma by liquid chromatography. The means and (SEM) of the steady-state concentrations (C-ss) of AMI, NTRIP, FLU, and NFLU we re 80.6 (14.2), 52.6 (10.3), 85.3 (16.1), and 90 (13.6) ng/mL, respect ively, and the apparent oral clearances (CL(or)) of AMI and FLU were 4 2.4 (8.6) and 14.9 (2.5) L/hr, respectively. The metabolite/drug stead y-state concentration ratio (C-ss(m)/C-ss) for NTRIP/AMI was 0.75 (0.1 4) and for NFLU/FLU was 1.27 (0.17). There was a significant correlati on (P < 0.05) between C-ss of FLU and that of AMI or NTRIP. The C-ss a nd (C-ss(m)/C-ss values obtained for AMI were higher (P < 0.056 and P < 0.0034, respectively) than those we observed in 10 patients treated solely with the same dose of AMI. The twofold increase in C-ss of AMI and ninefold increase in C-ss of NTRIP seem to be the result of inhibi tion of the metabolism of these compounds by FLU, particularly the rin g hydroxylation. Norfluoxetine may have a small inhibitory influence o n the metabolism of NTRIP but lacks this effect on the metabolism of A MI.