IMIPRAMINE AND ITS METABOLITES - RELATIONSHIP TO CEREBRAL CATECHOLAMINES IN RATS INVIVO

  • 1 January 1984
    • journal article
    • research article
    • Vol. 230  (2) , 330-335
Abstract
The relationship between blood and brain levels of imipramine (IMI) [tricyclic antidepressant], and its demethylated and hydroxylated metabolites was studied in rats after chronic administration of IMI. The combined concentration of IMI and its metabolites was .apprx. 10-fold higher in brain than in plasma and this ratio was independent of the dose or the time of sacrifice. However, the brain-to-plasma ratio for the individual compounds varied with the time of sacrifice after the last IMI dose. The metabolite, didesmethylimipramine, was found in significant quantities in plasma and brain tissue with a distribution similar to desmethylimipramine. The hydroxylated metabolites constituted < 6% of the combined concentration of IMI and its metabolites in plasma. Small amounts of 2-OH-desmethylimipramine were found in brain but 2-OH-IMI was rarely detected in cerebral tissue. With the exception of the hypothalamus, there were no significant differences in the IMI distribution or its metabolites among various brain regions. The relationship between the IMI concentrations, or its active metabolites in plasma or brain, and the extracellular availability of cerebral norepinephrine was also studied and found to be nonlinear; the norepinephrine concentration in the cerebroventricular fluid approached a maximal value when the combined concentration of IMI and its metabolites was 10 .mu.g/g in the brain or 1.5 .mu.g/ml in plasma. Cerebroventricular application of IMI or each of its metabolites resulted in an increased concentration of norepinephrine and dopamine in the cerebroventricular fluid; the concentrations of catecholamine metabolites remained unchanged. IMI or each of its metabolites apparently inhibits reuptake of cerebral catecholamines in vivo without affecting catecholamine metabolism immediately.