No abstract

Pharmacokinetics of imipramine (IMI) and its active metabolite, desipramine (DMI) was studied in rats after administration of a single dose of 10 mg/kg IMI, or after chronic administration of this dose once or twice a day for 14 days. The elimination curves of IMI and DMI from the blood and brain show that both the whole body and the brain behave as multi-compartment systems. Maximum concentrations of IMI and DMI in blood and brain appear at the same time, indicating rapid metabolism of IMI: the concentrations were significantly higher in the brain than in the blood. After the chronic treatment the maximum blood and cerebral levels of IMI and DMI were not much higher than after a single dose, but the elimination was slowed down. Brain concentration of IMI and DMI and brain IMI/DMI concentration ratio do not parallel those in the blood. After a prolonged treatment, once or twice a day, desipramine in the brain is present for the whole period between injections at concentrations sufficient to inhibit the noradrenaline uptake. If the drug is given twice a day, in addition to DMI also IMI is present for the whole time at concentration which may inhibit also serotonin uptake.

The chronic administration of imipramine (IMI; 10 mg/kg orally, twice daily for 14 days) enhanced the flexor reflex of the hind limb in the spinal rat. This effect was maintained for at least 72 h after termination of drug administration. Phenoxybenzamine but not cyproheptadine abolished the enhanced activity of the flexor reflex. After chronic administration of IMI high levels of desipramine (DMI) were found in the spinal cord, whereas IMI was not detectable there. No correlation was found between the levels of DMI in the spinal cord and the enhancement of the flexor reflex amplitude. A single i.v. dose of DMI facilitated the flexor reflex for a short period of time. In rats treated chronically with IMI, the binding of 3H-prazosin, a ligand of alpha 1-adrenoceptors, to spinal cord tissue was increased. The present results are a further argument for the previously advanced hypothesis that chronic administration of antidepressant drugs leads to an enhanced noradrenergic transmission, probably by increasing the number of alpha 1-adrenoceptors.