Changes in Amitriptyline Distribution in Rat Brain during a 14-Day Continuous Infusion

Kurata, Kouichi; Kurachi, Masayoshi; Tanii, Yasuyuki

doi:10.1159/000138532

Cited by 3 publications

(1 citation statement)

References 22 publications

(38 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The metabolism also depends on substrate concentrations and on hepatic activity, which vary with the conditions of administration Melzacka et a f , 1987). Also, changes in tissue distribution of metabolites of amitriptyline (AMI) have been reported during long-term infusion of this drug (Kurata et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

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

François¹,

Fialip²,

Eschalier³

et al. 1994

Fundamemntal Clinical Pharma

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%