Effects of lithium on alterations of pharmacokinetics of imipramine and on the related changes of monoamines in rat brain
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Desipramine
Gram, Lars F.; Bjerre, Marianne; Kragh-Sorensen, Per; Kvinesdal, Birgit; Molin, Jeanne; Pedersen, Ove L.; Reisby, Niels
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Abstract Chronic intraperitoneal administration of desipramine led to an extensive cumulation of the drug in brain and blood compared with that after a single dose treatment, while chronic treatment with desipramine by the oral route produced a brain concentration comparable with its level after a single oral dose. Comparison of the present results with the corresponding data of published imipramine pharmacokinetics indicated that the cumulation of desipramine in the rat brain was nearly the same when rats received desipramine or imipramine twice a day for two weeks at a dose of 10 mg kg−1 orally, or imipramine, twice a day for two weeks at a dose of 10 mg kg−1 intraperitoneally. It is suggested that these three experimental paradigms may be used as models for differentiation of the pharmacological effects of imipramine and desipramine in-vivo.
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The possibility that desipramine might prove to be a rapidly acting antidepressant was first raised by laboratory studies. In 1959 desipramine was isolated as a metabolite of imipramine (Hermann et al., 1959; Hermann and Pulver, 1960), and a series of papers then followed (Brodie et al., 1961; Gillette et al., 1961; Sulser et al., 1962) in which it was shown that reserpine-induced inactivity in the rat can be more rapidly reversed by desipramine than by imipramine. This was referred to (Gillette et al., 1961) as an experimental demonstration of the relative rapidity of the “antidepressant” action of the two drugs. Other experimental reports should however warn against incautious interpretation of laboratory findings. Garattini et al . (1962) showed that desipramine is not responsible for all the actions of imipramine: in mice, leptazol convulsions are inhibited by the latter but not by the former drug. Dingell et al . (1964) were able to show considerable species differences in the rate at which imipramine is converted to desipramine and in the rate at which desipramine is then destroyed. Their paper also emphasizes the paucity of information on the metabolism of imipramine in human subjects.
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• In a double-blind study of depressed patients treated with imipramine hydrochloride, levels of imipramine and desipramine were measured in plasma and in CSF. Levels of both drugs in CSF were approximately 10% of plasma levels, but the levels in the two body fluids were highly correlated. The levels of both drugs were approximately equal in plasma, but desipramine predominated in CSF (imipramine/desipramine ratio of 0.8). The imipramine-induced alteration in CSF levels of the serotonin metabolite (5-hydroxy-indoleacetic acid [5HIAA]) correlated with imipramine levels but not with desipramine. For the group of patients showing a clear antidepressant response, the mean drug levels were nearly double those of the nonresponder group, a difference that did not quite reach statistical significance in this relatively small sample. The desipramine levels showed no responder-nonresponder difference, while theratioof imipramine/desipramine was significantly higher among the responders. On the average this particular patient group had relatively low pretreatment levels of 5HIAA in CSF, an observation that may partially account for the relatively low overall response rate to imipramine.
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Plasma or serum concentrations of imipramine and five of its nonconjugated metabolites (desipramine, 2-OH-imipramine, 2-OH-desipramine, imipramine-N-oxide, and didesipramine) were followed in three cases of imipramine overdose and during steady state in 24 patients on continuous imipramine treatment. In the overdose cases the imipramine and desipramine concentrations declined monoexponentially with t 1/2s of 12 to 21 and 31 to 37 hr. The 2-OH-imipramine and 2-OH-desipramine levels were lower and declined in parallel with their corresponding parent compounds. In the patients on continuous imipramine treatment, the steady-state levels of 2-OH-imipramine and 2-OH-desipramine were very low or immeasurable (less than 15 nmol/l) in five patients. In most patients (n = 18) the hydroxymetabolite levels were much higher with 2-OH-imipramine/imipramine ratios of 0.09 to 0.45 and 2-OH-desipramine/desipramine ratios of 0.36 to 0.86. In one patient there were particularly high ratios (2-OH-imipramine/imipramine, 0.85; 2-OH-desipramine/desipramine, 1.30). The patients with very low hydroxymetabolite levels had considerably higher desipramine levels than the others, indicating that the low metabolite levels were due to poor hydroxylation. In one of these poor hydroxylators a desipramine t 1/2 of about 120 hr was estimated after imipramine discontinuation. With increased imipramine dose the 2-OH-imipramine levels tended to rise little or not at all. Imipramine-N-oxide could only be detected in the overdose cases during the first 6 to 12 hr and didesipramine was generally present only when the desipramine levels were above 200 nmol/l.
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Abstract Regional distribution of imipramine, desipramine and specific [3H]desipramine binding sites in the rat brain after acute and chronic treatment of rats with imipramine has been investigated. Both substances were distributed unevenly within rat brain after single and prolonged administration of imipramine. This was partly connected with the regional cerebral blood flow, lipid content in the regions and lipophilicity of the substances investigated. It was also found that the number of specific [3H]desipramine binding sites was different in the various brain areas, and that prolonged administration of imipramine led to a decrease of their number in some of those regions. No correlation was found between the regional cerebral distribution of desipramine and the regional density of specific [3H]desipramine binding sites.
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Abstract Imipramine and desipramine injected intracerebrally increase the temperature of fully reserpinised rats. Desipramine is more effective than imipramine in this. The effect of imipramine seems to be independent of the formation of desipramine in the brain. That imipramine, injected intraperitoneally, leads to an accumulation of brain desipramine has been confirmed.
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