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After 3 weeks treatment with imipramine (7.5 mg/kg/ip), 5-hydroxytryptamine uptake in rat brain homogenates was not affected whereas noradrenaline uptake was lowered. This result could be explain by metabolism of imipramine producing desipramine.
A study of the cytochrome P-450 level and imipramine (IMI) demethylase activity in liver microsomes of rats treated concurrently with IMI and chlorpromazine (CPZ) or IMI and chlorprothixene (CPX) for two weeks were carried out. Concomitant administration of IMI and CPZ or IMI and CPX elevated the cytochrome P-450 level and accelerated IMI demethylation in in vitro study. Kinetic study of IMI demethylation carried out in the absence or in the presence of CPZ or CPX revealed that those neuroleptics inhibited IMI demethylation via competitive mechanism. Simultaneously with the enzymatic study the brain level of IMI and its demethylated metabolite desipramine (DMI) was assessed. It was found that 1 hr after withdrawal of IMI and CPZ or IMI and CPX the brain level of IMI was elevated in comparison with that of IMI treated animals, and the ratio between DMI/IMI brain concentration was decreased. When the assessment of IMI and DMI brain level was performed 24 hr after withdrawal of IMI and CPZ or IMI and CPX, there was no difference between the concentration of IMI and DMI in both, experimental and control animals.
The effects of subchronic administration of imipramine (IMIP), chlorpromazine (CPZ) and the combination of IMIP + CPZ on 3H-IMIP binding of rat blood platelets and cortex were studied. All three treatments decreased the number of IMIP binding sites (Bmax) of rat blood platelets and cortex. The combination produced a significantly greater decrease in Bmax in platelets than either treatment alone; a similar trend in cortex was observed. The effect of some neuroleptics on 3H-IMIP binding sites may be relevant to their antidepressant action. These results, together with previous evidence that the combination has a synergistic effect on down regulation of brain serotonin-2 (5-HT2) receptors, suggest that changes in serotonergic neurotransmission may be relevant to the enhanced efficacy of the combination of tricyclic antidepressants and neuroleptics, compared to either type of drug alone, in the treatment of delusional depression.
1 The effect of imipramine (Imip) in concentrations between 10(-7)M and 5 X 10(-5)M has been studied on rat atrial transmembrane potentials. In another group of experiments the effect of Imip was studied in atrial fibres from rats pretreated for 24 days with twice daily intraperitoneal injections of Imip 7.5 mg/kg or saline. 2 In non-treated atria Imip depressed action potential amplitude and Vmax, reduced th e resting membrane potential and shifted the membrane responsiveness and recovery time curves downward and to the right. 3 Imip also prolonged the action potential duration and the effective refractory period, lengthening the effective refractory period relative to action potential duration. 4 Pretreatment with Imip decreased the resting membrane potential, amplitude and Vmax of the action potential and prolonged the effective refractory period. Further addition of Imip produced similar but more marked changes than in non-treated animals. 5 Imip suppressed the spontaneous atrial automaticity as well as the abnormal automaticity induced by BaCl2, aconitine, ouabain or isoprenaline. 6 The drug produced a negative inotropic effect and depressed the amplitude of the slow contractions elicited by isoprenaline in K-depolarized atria. 7 It is concluded that even when the effects of Imip are similar to those of quinidine (group I of antiarrythmics), it also produces a reduction in Ca and K conductances.
Daily variations in the pharmacokinetics of imipramine (IMI) could contribute to circadian phase-dependent effects of the drug. Therefore, the chronopharmacokinetics of IMI and its metabolite, desipramine (DMI), were studied after single and chronic application. Male rats were synchronized to a 12:12 hour light:dark (L:D) regimen with lights on from 07:00 to 19:00 (dark, 19:00-07:00). In single-dose experiments rats were injected with IMI (10 mg/kg) i.p. or i.v. at 07:30 or 19:30 and groups of rats were killed 0-22 hours thereafter. After chronic application of IMI in drinking water (approximately 15 mg/kg/d) groups of rats were killed during the 14th day of treatment at 02:00, 08:00, 14:00, and 20:00, respectively. Brain and plasma concentrations of IMI and DMI were determined by reversed-phase high-performance liquid chromatography with ultraviolet detection. After single i.p. application of IMI, maximal brain concentrations (Cmax) of IMI and DMI were nearly twofold higher in darkness (IMI, 4.8 micrograms/g; DMI, 1.8 micrograms/g) than in light (IMI, 2.85 micrograms/g; DMI, 0.85 microgram/g). Also, the area under the curve (AUC) (0-22 hours) was about 1.6-fold greater in darkness than in light for IMI and DMI; half-lives were not circadian phase dependent. After i.v. injection of IMI, the AUC in brain was also about 30% greater in darkness than in light. After chronic application of IMI in drinking water, brain concentrations of IMI and DMI varied more than threefold within 24 hours. The data demonstrate that the pharmacokinetics of IMI and DMI are circadian phase dependent. It is assumed that circadian variations in drug distribution are more likely to contribute to the drug's chronopharmacokinetics than variations in the drug's metabolism. The 24-hour variations in the drug's concentrations after chronic IMI application in drinking water can be explained by the drinking behavior of the rats, which by itself is altered by IMI.
Concentrations of imipramine (IMI) and desipramine (DMI) in the rat brain after administration of IMI in aqueous solution by stomach gauge twice daily, in oil solution parenterally at 48 h intervals, and with drinking water were assayed. IMI administration with the drinking water for 21 days produced a pattern of the brain concentrations of IMI and DMI similar to that observed in rats receiving IMI by stomach tube for two weeks, at 12 h intervals. When IMI was given to rats ip in an oil solution at 48 h intervals for 10 days, the brain levels of both IMI and DMI were very high and rather stable during 48 h after administration of the last dose of IMI. However, the relation between brain concentration of IMI and DMI differed markedly from that found in rats receiving IMI with the drinking water. It seems that administration of IMI with drinking water may be recommended as a reliable and convenient dosage schedule in experiments which need prolonged treatment with IMI.
The regional distribution of imipramine (IMI) and desipramine (DMI) in rat brain after single and chronic oral administration of IMI was studied. The distribution of IMI and DMI in all examined brain regions was similar, except for hippocampus + septum. After chronic administration of IMI the disappearance of the parent drug and its metabolite was slowing down in all investigated brain regions as well as in the plasma. The accumulation of IMI and DMI after chronic treatment of IMI was significantly higher in plasma than in all examined brain regions.
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