Plasma and Brain Pharmacokinetics of Amitriptyline and Its Demethylated and Hydroxylated Metabolites After Acute Intraperitoneal Injection in Mice

Overview

Journal Eur J Drug Metab Pharmacokinet

Date 1994 Jan 1

PMID 7957453

Citations 2

Authors

F Coudore

J Fialip

A Eschalier

J Lavarenne

Affiliations

Soon will be listed here.

Abstract

The fate of amitriptyline (AMI) and its demethylated and hydroxylated metabolites was studied in Swiss CD1 mice, after acute intraperitoneal injection of AMI (20 mg/kg). Levels of each compound were determined to establish pharmacokinetic parameters in plasma and brain. Absorption and elimination of AMI were rapid (tmax = 0.37 h and 0.42 h, and t1/2 = 3.2 h and 3.6 h in plasma and brain, respectively). In plasma, 10-OH-nortriptyline was the main metabolite (46% of AUC) and 10-OH-amitriptyline reached significant levels but only during the first hour. In brain, AMI (43% of total AUC), nortriptyline (NOR) (29%) and demethylnortriptyline (DM-NOR) (11%) were the most abundant compounds, possibly through high blood-brain barrier transfer and/or marked intracerebral demethylation. Brain OH-metabolite levels were much lower. Knowledge of kinetic parameters and metabolism of AMI can help in the evaluation of pharmacological activity.

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References

Kruger R, Holzl G, Kuss H, Schefold L . Comparison of the metabolism of the three antidepressants amitriptyline, imipramine, and chlorimipramine in vitro in rat liver microsomes. Psychopharmacology (Berl). 1986; 88(4):505-13. DOI: 10.1007/BF00178516. View

Fialip J, Makambila M, Rigal F, Devoize J, Varoquaux O, Eschalier A . Chronic administration of clomipramine inhibits morphine hot plate analgesia. Life Sci. 1986; 38(12):1097-103. DOI: 10.1016/0024-3205(86)90245-6. View

Potter W, Calil H, Manian A, Zavadil A, Goodwin F . Hydroxylated metabolites of tricyclic antidepressants: preclinical assessment of activity. Biol Psychiatry. 1979; 14(4):601-13. View

Sumirtapura Y, Leroux Y, Komar A, Cano J, Gaillot J . Pharmacokinetics of metapramine (19560 RP) in man after infusion and intravenous injection. Eur J Clin Pharmacol. 1983; 25(5):673-7. DOI: 10.1007/BF00542357. View

Le Blanc P, Dumas J . [Calculation of initial values of pharmacokinetic using a programmable calculator]. Therapie. 1983; 38(1):21-6. View

Potter W, Rudorfer M, Lane E . Active metabolites of antidepressants: pharmacodynamics and relevant pharmacokinetics. Adv Biochem Psychopharmacol. 1984; 39:373-90. View

Vandel B, SANDOZ M, VANDEL S, ALLERS G, VOLMAT R . Biotransformation of amitriptyline in depressive patients: urinary excretion of seven metabolites. Eur J Clin Pharmacol. 1982; 22(3):239-45. DOI: 10.1007/BF00545222. View

Della Corte L, Broadhurst A, Sgaragli G, Filippini S, HEELEY A, JAMES H . Clinical response and tricyclic plasma levels during treatment with clomipramine. Br J Psychiatry. 1979; 134:390-400. DOI: 10.1192/bjp.134.4.390. View

Bougerolle A, Chabard J, Dordain G, Frydman A, Gaillot J, Piron J . Kinetics of metapramine and its demethylated metabolites after single and chronic oral administration in man. Eur J Drug Metab Pharmacokinet. 1986; 11(2):113-8. DOI: 10.1007/BF03189836. View

10.

Bougerolle A, Chabard J, Eschalier A, Aumaitre O, Fialip J, Dordain G . Pharmacokinetics of metapramine and its demethylated metabolites in plasma and brain of mice. Fundam Clin Pharmacol. 1989; 3(5):515-25. DOI: 10.1111/j.1472-8206.1989.tb00686.x. View

11.

Cassano G, Sjostrand S, Hansson E . Distribution and fate of C-14-amitriptyline in mice and rats. Psychopharmacologia. 1965; 8(1):1-11. DOI: 10.1007/BF00405356. View

12.

Breyer-Pfaff U, PROX A, WACHSMUTH H, Yao P . Phenolic metabolites of amitriptyline and nortriptyline in rat bile. Drug Metab Dispos. 1987; 15(6):882-9. View

13.

Glotzbach R, Preskorn S . Brain concentrations of tricyclic antidepressants: single-dose kinetics and relationship to plasma concentrations in chronically dosed rats. Psychopharmacology (Berl). 1982; 78(1):25-7. DOI: 10.1007/BF00470582. View

14.

Schulz P, Dick P, Blaschke T, HOLLISTER L . Discrepancies between pharmacokinetic studies of amitriptyline. Clin Pharmacokinet. 1985; 10(3):257-68. DOI: 10.2165/00003088-198510030-00005. View

15.

Baumann P, Gaillard J, Gerber C, Bouras C . Evaluation of the levels of free and total amitriptyline and metabolites in the plasma and brain of the rat after long-term administration of doses used in receptor studies. Psychopharmacology (Berl). 1984; 84(4):489-95. DOI: 10.1007/BF00431455. View

16.

Marty H, Varoquaux O, Fialip J, Cordonnier P, DUROUX E, Bulach C . Compared plasma and brain pharmacokinetics of clomipramine and its metabolite demethylclomipramine in two strains of mice (NMRI and CD1). Fundam Clin Pharmacol. 1992; 6(2):49-57. DOI: 10.1111/j.1472-8206.1992.tb00094.x. View

17.

Hyttel J, Christensen A, Fjalland B . Neuropharmacological properties of amitriptyline, nortriptyline and their metabolites. Acta Pharmacol Toxicol (Copenh). 1980; 47(1):53-7. DOI: 10.1111/j.1600-0773.1980.tb02025.x. View

18.

Fialip J, Marty H, Makambila M, Civiale M, Eschalier A . Pharmacokinetic patterns of repeated administration of antidepressants in animals. II. Their relevance in a study of the influence of clomipramine on morphine analgesia in mice. J Pharmacol Exp Ther. 1989; 248(2):747-51. View

19.

Law B . Analysis of basic compounds on a silica column with an aqueous methanol eluent. The use of quantitative structure-retention relationships in metabolite identification. J Chromatogr. 1987; 407:1-18. DOI: 10.1016/s0021-9673(01)92600-7. View

20.

ONeill K, Valentino D . Chronic desipramine attenuates morphine analgesia. Pharmacol Biochem Behav. 1986; 24(1):155-8. DOI: 10.1016/0091-3057(86)90061-4. View