Measurement and pharmacokinetic analysis of imipramine and its metabolite by brain microdialysis

Sato, Yoichiro; Shibanoki, Shinji; Sugahara, Megumi; Ito, Koichi

doi:10.1111/j.1476-5381.1994.tb13120.x

Cited by 28 publications

(11 citation statements)

References 19 publications

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“…This study was designed to investigate the pharmacokinetics of escitalopram including its temporal plasma-brain kinetic inter-relationship in conscious rats by using intracerebral microdialysis in conjunction with regular blood sampling. There are some reports of antidepressant drug disposition in rat brain using microdialysis [28][29][30][31][32][33]. However, the quantitative pharmacokinetic information from these studies is limited, due to a lack of correction for microdialysis probe recovery in vivo, an insufficient duration of the experiment to describe fully the distribution and elimination of the drug under investigation, or a lack of analytical sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic modelling of blood–brain barrier transport of escitalopram in rats

Bundgaard

Jørgensen

Larsen

2007

Biopharm & Drug Disp

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This study examined the pharmacokinetics and distribution of escitalopram in the brain extracellular fluid in rats by the concurrent use of intracerebral microdialysis and serial blood sampling. Following three constant intravenous infusions, drug concentrations in the hippocampus and plasma were monitored for 6 h. To estimate the integrated pharmacokinetics and intercompartmental transport parameters, including blood-brain barrier (BBB) transport over the entire dose range, unbound brain and plasma escitalopram concentration data from all doses were simultaneously analysed using compartmental modelling. The pharmacokinetic analysis revealed that systemic clearance decreased as a function of dose, which was incorporated in the integrated model. Escitalopram was rapidly and extensively transported across the BBB and distributed into the brain extracellular fluid. The modelling resulted in an estimated influx clearance into the brain of 535 microl/min/g brain, resulting in an unbound brain-to-plasma AUC ratio of 0.8 independent of escitalopram dose. The model may be applied for preclinical evaluations or predictions of escitalopram concentration-time courses in plasma as well as at the target site in the CNS for various dosing scenarios. In addition, this modelling approach may also be valuable for studying BBB transport characteristics for other psychotropic agents.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic modelling of blood–brain barrier transport of escitalopram in rats

Bundgaard

Jørgensen

Larsen

2007

Biopharm & Drug Disp

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“…As the diffusion properties of compounds in brain tissue are likely to be different from in vitro conditions, dialysate values were not corrected to account for the in vitro recovery rate of the probe. However, it was possible to directly compare the uncorrected dialysate concentrations between the groups as there was no statistical difference between in vitro probe recovery rates across the groups (Table 1), thus ensuring comparisons were valid as previously reported (Sato et al ., 1994; Evrard et al ., 1998; Page and Lucki, 2002; Page et al ., 2010).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of P‐glycoprotein enhances transport of imipramine across the blood–brain barrier: microdialysis studies in conscious freely moving rats

O’Brien

Clarke

Fitzgerald

et al. 2012

British J Pharmacology

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BACKGROUND AND PURPOSERecent studies indicate that efflux of antidepressants by the multidrug resistance transporter P-glycoprotein (P-gp) at the blood-brain barrier (BBB) may contribute to treatment-resistant depression (TRD) by limiting intracerebral antidepressant concentrations. In addition, clinical experience shows that adjunctive treatment with the P-gp inhibitor verapamil may improve the clinical outcome in TRD. Therefore, the present study aimed to investigate the effect of P-gp inhibition on the transport of the tricyclic antidepressant imipramine and its active metabolite desipramine across the BBB. EXPERIMENTAL APPROACHIntracerebral microdialysis in rats was used to monitor brain levels of imipramine and desipramine following i.v. imipramine administration, with or without pretreatment with one of the P-gp inhibitors verapamil or cyclosporin A (CsA). Plasma drug levels were also determined at regular intervals. KEY RESULTSPretreatment with either verapamil or CsA resulted in significant increases in imipramine concentrations in the microdialysis samples, without altering imipramine plasma pharmacokinetics. Furthermore, pretreatment with verapamil, but not CsA, led to a significant elevation in plasma and brain levels of desipramine. CONCLUSIONS AND IMPLICATIONSThe present study demonstrated that P-gp inhibition enhanced the intracerebral concentration of imipramine , thus supporting the hypothesis that P-gp activity restricts brain levels of certain antidepressants, including imipramine. These findings may help to explain reports of a beneficial response to adjunctive therapy with verapamil in TRD. AbbreviationsAUC, area under the concentration-time curve; BBB, blood-brain barrier; C0, initial concentration following bolus intravenous administration; Cl, drug clearance from plasma; CsA, cyclosporin A; ECF, extracellular fluid; HPLC-ECD, high performance liquid chromatography with electrochemical detection; kel, elimination rate constant; PFC, prefrontal cortex; P-gp, P-glycoprotein; PK, pharmacokinetic; SNP, single nucleotide polymorphism; t1/2, half-life of drug in plasma; TRD, treatment-resistant depression; Vd, volume of distribution BJP British Journal of Pharmacology

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“…Nevertheless, although other TCA (e.g. imipramine and desipramine) also present short intracerebral half-lives, 46,47) must be emphasized that when given once or twice a day for 14 d they are present in the brain for the whole interval between injections at concentrations sufficient to inhibit noradrenaline and serotonin uptake. 48) In contrast, the lowest dose (3 mg/kg) induced a significant, but transient, increase in total caloric intake.…”

Section: Discussionmentioning

confidence: 99%

Effect of Chronic Treatment with Clomipramine on Food Intake, Macronutrient Selection and Body Weight Gain in Rats

Calegari

Gorenstein

Gentil

et al. 2007

Biological & Pharmaceutical Bulletin

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Weight gain is a frequent side effect observed during drug treatment of psychiatric disorders.1) It often contributes towards patient non-compliance and discontinuation of the pharmacological treatment.2) Weight gain may also contribute to comorbidities such as hypertension, coronary heart disease, diabetes, and stroke. 3,4) Weight gain is also a relatively common problem during both acute and long-term treatment with antidepressants. It appears that tricyclic antidepressants (TCA) may be more likely to cause weight gain as compared to selective serotonin reuptake inhibitors (SSRIs), a class of antidepressant widely used in clinical practice. 5,6) Among them amitriptiline, doxepin, imipramine, trimipramine, maprotiline, nortriptyline, and clomipramine are reported to cause marked weight gain. 2)TCA may affect appetite by blocking the reuptake of serotonin and noradrenaline. Serotonin is recognized to have an influence on food intake and macronutrient selection. 7,8) Noradrenaline has also been shown to have an effect on food intake that opposes the effects of serotonin, but its effects on macronutrient selection are not clear. 7,9,10) TCA may also affect appetite by blocking histaminergic (H1) pathways. 11)However, the mechanisms underlying the weight gain induced by antidepressants treatment have yet to be understood. In clinical studies, it has been found that antidepressant drugs alter nutrient selection, inducing in particular a preference for high-carbohydrate or sweet foods. [12][13][14] Early efforts to model these effects in rats have led to contradictory results. For example, it has been shown that acute systemic injections of clomipramine selectively enhance carbohydrate intake.15) On the other hand, it has been reported that food intake was initially and significantly decreased by desmethylimipramine treatment but this effect progressively returned towards pretreatment levels over the course of the drug administration (30 d).16) Such discrepancies may be related to brain monoamine receptor neuroadaptations following chronic treatment with antidepressants.17-21) Nobrega and Coscina 22) evaluated the effects of the chronic treatment with two other TCA, amitriptyline and desipramine on food selection. They showed that desipramine decreased food intake and body weight, while amitriptiline did not change food intake and body weight or slightly reduced them in comparison to vehicle-treated controls. However, strict macronutrient protocols (using separate sources of pure macronutrients) have rarely been tested in rats following the chronic treatment with TCA. Therefore, it remains unclear whether this class of antidepressants change macronutrient selection and weight gain in rats. Given that and there is only limited evidence on the effects of TCA on macronutrient selection especially over long periods of drug treatment, the present study was carried out to explore the effects of chronic treatment with clomipramine (CMI) on food intake, macronutrient selection and body weight in male rats allowed to self-sel...

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Measurement and pharmacokinetic analysis of imipramine and its metabolite by brain microdialysis

Abstract: 1 The feasibility of the brain microdialysis method for direct measurement and pharmacokinetic study of imipramine (Imip) and its metabolite desipramine (DMI)

Cited by 28 publications

References 19 publications

Pharmacokinetic modelling of blood–brain barrier transport of escitalopram in rats

Pharmacokinetic modelling of blood–brain barrier transport of escitalopram in rats

Inhibition of P‐glycoprotein enhances transport of imipramine across the blood–brain barrier: microdialysis studies in conscious freely moving rats

Effect of Chronic Treatment with Clomipramine on Food Intake, Macronutrient Selection and Body Weight Gain in Rats

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