MICE PLASMA AND BRAIN PHARMACOKINETICS OF AMITRIPTYLINE AND ITS DEMETHYLATED AND HYDROXYLATED METABOLITES AFTER HALF-LIFE REPEATED ADMINISTRATION - COMPARISON WITH ACUTE ADMINISTRATION

Kinetics of amitriptyline (AMI), its demethylated metabolites nortript yline (NOR) and demethylnortriptyline (DM-NOR), and its hydroxylated m etabolites, the E and Z isomers or 10-hydroxy-amitriptyline (E- and Z- 10-OH-AMI) and of 10-hydroxynortriptyline (E- and Z-10-OH-NOR) were st udied in plasma and brain from Swiss CD1 mice after six successive int raperitoneal injections of amitriptyline (10 mg/kg) administered every elimination half-life time (t(1/2) = 3.1 h) to obtain the steady stat e. In these conditions, AMI was metabolised rapidly. Compared with acu te administration, hydroxylation reactions were saturated by the repea ted AMI injections and demethylation became preponderant both in plasm a and brain. Thus, plasma levels of demethylated metabolites, NOR and DM-NOR, increased (49% and 13% of total AUC against 22% acid 7% in acu te conditions, respectively), while levels of AMI and its hydroxylated metabolites, 10-OH-AMI and 10-OH-NOR, decreased (8%, 2.5% and 27.5% a gainst 17%, 8% and 46% in acute conditions, respectively). Likewise in brain tissue, when AMI was repeatedly administered, NOR and DM-NOR in creased (62% and 22% against 29% and 11%, respectively) while AMI and 10-OH-AMI decreased (11.5% and 1% against 47% and 9%, respectively). T hese differences may account for modified pharmacological effects seen after half-life repeated administration of AMI since demethylated met abolites exert a more marked inhibiting effect than AMI on noradrenali ne reuptake.