Mice plasma and brain pharmacokinetics of amitriptyline and its demethylated and hydroxylated metabolites after half‐life repeated administration. Comparison with acute administration

Abstract

Kinetics of amitriptyline (AMI), its demethylated metabolites nortriptyline (NOR) and demethylnortriptyline (DM-NOR), and its hydroxylated metabolites, 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 studied in plasma and brain from Swiss CD1 mice after six successive intraperitoneal injections of amitriptyline (10 mg/kg) administered every elimination half-life time (t1/2 = 3.1 h) to obtain the steady state. In these conditions, AMI was metabolised rapidly. Compared with acute administration, hydroxylation reactions were saturated by the repeated AMI injections and demethylation became preponderant both in plasma and brain. Thus, plasma levels of demethylated metabolites, NOR and DM-NOR, increased (49% and 13% of total AUC against 22% and 7% in acute conditions, respectively), while levels of AMI and its hydroxylated metabolites, 10-OH-AMI and 10-OH-NOR, decreased (8%, 2.5% and 27.5% against 17%, 8% and 46% in acute conditions, respectively). Likewise in brain tissue, when AMI was repeatedly administered, NOR and DM-NOR increased (62% and 22% against 29% and 11%, respectively) while AMI and 10-OH-AMI decreased (11.5% and 1% against 47% and 9%, respectively). These differences may account for modified pharmacological effects seen after half-life repeated administration of AMI since demethylated metabolites exert a more marked inhibiting effect than AMI on noradrenaline reuptake.

Chronic treatment with duloxetine is necessary for an anxiolytic-like response in the mouse zero maze: the role of the serotonin transporter

“…This difference in chronicity may explain the difference and suggests that length of treatment is an important factor. Furthermore, citalopram and amitriptyline have shorter plasma half-lives in mice (1.5 and 3.1 h, respectively, Coudore et al 1994;Fredricson 1982) compared to duloxetine (half-life ∼6 h, in-house data) and this is likely to lead to differences in drug exposure that may also be a crucial determinant (Benmansour et al 1999Pineyro and Blier 1999). However, despite these limitations, both citalopram and amitriptyline significantly reduced SERT density and attenuated the hypothermic response to 8-OHDPAT and mCPP suggesting that the chronic regimen used was sufficient to induce biochemical and physiological changes.…”

P-glycoprotein reduces the ability of amitriptyline metabolites to cross the blood brain barrier in mice after a 10-day administration of amitriptyline

“…Coudore et al (1994Coudore et al ( , 1996 studied plasma and brain pharmacokinetics of amitriptyline and its metabolites in mice and Permeability of the blood-brain barrier for amitriptyline 71 1&+ 1+&+ Amitriptyline Nortriptyline Figure 2 Chemical structures of amitriptyline and nortriptyline rats, showing that all drugs and metabolites that occur in the plasma can also be found in the brain, although in differing concentrations. After acute i.p.…”