The effects of imipramine on the methylation of phosphatidylethanolamine (PE) in the cortical membranes of Wistar rats.

This study investigates the effect of imipramine (IMI) on the methylation of phosphatidylethanolamine (PE) in crude cortical membranes of rat brain in vitro and ex vivo. It was found that IMI enhanced the formation of phosphatidyl-N-monomethylethanolamine (PME) and phosphatidyl-N,N-dimethylethanolamine (PDE) and inhibited the formation of phosphatidylcholine (PC) in the cortical membranes of rats in vitro. The same effect i.e. increased incorporation of methyl groups in PE and PME and decreased formation of PC was found in the cortical membrane of rats killed 1 hr after intraperitoneal administration of IMI at a single dose of 10 mg/kg. Chronic treatment of rats with IMI for 14 days with a daily dose of 10 mg/kg i.p. led to further inhibition of PC formation but did not affect the formation of PME and PDE and abolished the stimulating effect of IMI on the formation of PME and PDE in vitro.

Effect of imipramine on the membrane anisotropy and on the phospholipid methylation in the central nervous system of the rat.

An ex-vivo and in-vitro study of the effects of imipramine on the membrane anisotropy and phospholipid methylation in the rat cortical membranes was carried out. A comparative study of the membrane fluidity in various brain regions indicated different basal anisotropy of the areas and different reaction of these membranes to imipramine. It was found that imipramine when given to rats chronically (14 x 10 mg kg-1, i.p.) or added externally to the cortical membranes of naive rats or rats treated with a single dose of imipramine (10 mg kg-1, i.p.) decreased the anisotropy of cortical membranes. Chronic imipramine produced some changes of the membrane architecture in the cortex, whereas imipramine in different concentrations did not fluidize these membranes in-vitro. Imipramine in concentrations corresponding to its mean concentration in the rat brain after administration at a dose of 10 mg kg-1 i.p., potentiated phospholipid methylation in the cortical membranes of naive rats and rats receiving imipramine in a single dose of 10 mg kg-1 i.p. in an in-vitro study, whereas the prolonged administration of imipramine decreased the sensitivity of phospholipid methyltransferases to the stimulating effect of the drug in-vitro.

Effect of some cationic amphiphilic drugs on phospholipid methylation in the central nervous system of rats.

Imipramine, desipramine, citalopram and chlorpromazine in concentrations which corresponded with their concentration in the central nervous system of rats after pharmacological doses, potentiated phospholipid methylation in the synaptic cortical membranes of naive rats in-vitro. Chronic administration of imipramine, desipramine or citalopram induced changes in the activity of phospholipid methyltransferases since none of these drugs stimulated phospholipid methylation in the synaptic cortical membranes of rats treated with these antidepressants for two weeks. In contrast, chronic treatment with chlorpromazine did not change the sensitivity of phospholipid methyltransferases to the stimulating effect of chlorpromazine, whereas addition of haloperidol to the synaptic cortical membranes of rats treated chronically with haloperidol led to a decrease of phospholipid methylation.

Regional distribution of imipramine, desipramine and specific [3H]desipramine binding sites in the rat brain after acute and chronic treatment with imipramine.

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.

Cerebral pharmacokinetics of ipsapirone in rats after different routes of administration.

Ipsapirone, a putative non-benzodiazepine anxiolytic, was extensively metabolized in rats to 1-(2-pyrimidinyl)piperazine (1-PP) which accumulated in the brain. Neither the route of administration (i.p. or p.o.), nor prolonged administration of ipsapirone or 1-PP affected their accumulation in the rat brain. The cytochrome P450 level and ethylmorphine N-demethylase activity in rat liver microsomes were unchanged by chronic treatment with ipsapirone or 1-PP. The results indicate that 1-PP may contribute to the alpha 2-adrenoceptor antagonism of ipsapirone in rats and that chronic treatment with the drug does not affect its biotransformation to 1-PP.

Species differences in hepatic microsomal drug-metabolizing enzymes.

The activity of some metabolizing enzymes was assessed in the liver microsomes of Acomys cahirinus, mice and rats. The enzymatic studies were followed by the determination of cerebral level of apomorphine (APO), imipramine (IMI) and its metabolite desipramine (DMI) of animals treated with a single dose of APO or IMI. It was found that the level of cytochrome P-450 and the activity of IMI demethylase and glucuronyltransferase in the liver microsomes of rats was significantly higher than those in the liver microsomes of Acomys and mice. The brain levels of APO, IMI and DMI were different in investigated species and IMI and DMI levels in the brain of Acomys, mice and rats corresponded to the activity of IMI demethylase in the liver microsomes of these species.