Pharmacokinetics of Amitriptyline and its Demethylated Metabolite in Serum and Specific Brain Regions of Rats After Acute and Chronic Administration of Amitriptyline

Abstract

The concentrations of amitriptyline (AMT) and its demethylated metabolite nortriptyline (NRT) in the serum and in specific brain regions were determined periodically after acute or chronic administration of 20 mg/kg of AMT in rats. Both AMT and NRT declined from the serum in a biexponential manner and were eliminated monoexponentially from the brain regions, with no significant difference in elimination among the eight brain regions examined. In the brain, both AMT and NRT were unevenly distributed after chronic administration, whereas an even distribution was observed after acute administration. The AUCbrain:AUCserum ratio of AMT was higher than that of NRT, indicating greater transport of AMT into the brain regions. The AUCAMT value in the serum increased 1.6 times after chronic administration, whereas no significant changes were observed in the brain regions. The AUCNRT values increased 9.0 times in the serum and 6.8 times in the brain, with the increase in the serum being greater. These results suggest inhibited distribution of the drugs into the tissues, including the brain regions, and enhanced metabolism of AMT.

Tricyclic Antidepressant Amitriptyline-induced Glial Cell Line-derived Neurotrophic Factor Production Involves Pertussis Toxin-sensitive Gαi/o Activation in Astroglial Cells

“…In fact, it has been previously shown that the concentration of amitriptyline in the brain is ϳ10 -35 times higher than the plasma concentration of amitriptyline (60,61). The therapeutic plasma concentration of amitriptyline is commonly regarded to range from ϳ0.36 to 0.9 M (62).…”

Antidepressants Increase Glial Cell Line-Derived Neurotrophic Factor Production through Monoamine-Independent Activation of Protein Tyrosine Kinase and Extracellular Signal-Regulated Kinase in Glial Cells

“…Furthermore, it has been reported that most antidepressants accumulate in the brain because they have highly lipophilic properties (Prouty and Anderson, 1990). For example, the brain concentration of amitriptyline is approximately 10 to 35 times higher than the corresponding blood levels (Glotzbach and Preskorn, 1982;Baumann et al, 1984;Miyake et al, 1990), although the therapeutic plasma concentrations of amitriptyline range approximately from 0.36 to 0.9 M (Baldessarini, 2001). In addition, the mean brain concentrations of the tricyclic antidepressants in post-mortem humans were approximately 20 times higher than the corresponding blood levels (Prouty and Anderson, 1990).…”

Inhibition of Astroglial Inwardly Rectifying Kir4.1 Channels by a Tricyclic Antidepressant, Nortriptyline

“…These observations suggest that the astroglial Kir4.1 channels could be a common target for TCAs. Although the K d value of nortriptyline (28.3 M at E K ) was considerably higher than the clinical plasma concentrations of TCAs (e.g., nortriptyline, 0.2ϳ0.6 M; amitriptyline, 0.4ϳ0.9 M; imipramine, 0.7ϳ1.1 M; desipramine, 0.5ϳ1.1 M) (Baldessarini, 2001;Kobayashi et al, 2004), it is known that cerebral concentrations of TCAs reach values much higher than those in the plasma due to their high brain/plasma distribution ratios of 10:1 to 30:1 (Glotzbach and Preskorn, 1982;Baumann et al, 1983Baumann et al, , 1984Miyake et al, 1990;Besret et al, 1996). Furthermore, because most of the TCAs have relatively slow elimination rates (e.g., nortriptyline, t 1/2 ϭ 22-88 h) (Sanchez and Hyttel, 1999), their plasma concentrations can easily be elevated upon overdosage (Rosenstein et al, 1993;Barbey and Roose, 1998).…”