Imipramine Plasma Research Articles

Population pharmacokinetic study of imipramine in Taiwan people healthy volunteers

Imipramine is an antidepressant drug (ADs) that shows therapeutic efficacy in a maximum of 60–80% of patients who have experienced a major depressive episode (unipolar or bipolar). The purpose of the study was to investigate the pharmacokinetics of a multi-oral dose of Imipramine 25 mg tablet in a Taiwan healthy population. The study was a standard two-way, crossover, randomized, and single dose daily for 5 days study with a two-week washout period in 30 healthy volunteers who received 25 mg imipramine tablets (test and reference formulation). After drug administration, blood samples were taken according to the planned times over a period of 24 hours. The plasma concentrations of Imipramine were determined using the validated high-performance liquid chromatography method with ultraviolet detection. All the pharmacokinetic parameters for Imipramine in healthy volunteers were calculated using nonlinear mixed-effect modeling and standard non-compartmental methods. Values (relative standard error (RSE) %) for first-order absorption rate constant (Ka), oral clearance (Cl/F), and apparent volume of distribution (Vd/F) were 1.05 (7.11) 1/h, 6.99(0.27) L/h, and 71.7.9(4.80) L. The median for the time to peak plasma Imipramine concentration (Tmax) for the test and reference drug was 2(1.1-4) hours and 4(1.9-5) hours respectively. In conclusion, the imipramine pharmacokinetic model in the Taiwan healthy population was similar to other studied populations.

Physiologically Based Pharmacokinetic Model of Brain Delivery of Plasma Protein Bound Drugs

IntroductionA physiologically based pharmacokinetic (PBPK) model is developed that focuses on the kinetic parameters of drug association and dissociation with albumin, alpha-1 acid glycoprotein (AGP), and brain tissue proteins, as well as drug permeability at the blood–brain barrier, drug metabolism, and brain blood flow.GoalThe model evaluates the extent to which plasma protein-mediated uptake (PMU) of drugs by brain influences the concentration of free drug both within the brain capillary compartment in vivo and the brain compartment. The model also studies the effect of drug binding to brain tissue proteins on the concentration of free drug in brain.MethodsThe steady state and non-steady state PBPK models are comprised of 11–12 variables, and 18–23 parameters, respectively. Two model drugs are analyzed: propranolol, which undergoes modest PMU from the AGP-bound pool, and imipramine, which undergoes a high degree of PMU from both the albumin-bound and AGP-bound pools in plasma.ResultsThe free propranolol concentration in brain is under-estimated 2- to fourfold by in vitro measurements of free plasma propranolol, and the free imipramine concentration in brain is under-estimated by 18- to 31-fold by in vitro measurements of free imipramine in plasma. The free drug concentration in brain in vivo is independent of drug binding to brain tissue proteins.ConclusionsIn vitro measurement of free drug concentration in plasma under-estimates the free drug in brain in vivo if PMU in vivo from either the albumin and/or the AGP pools in plasma takes place at the BBB surface.

Low-toxic air-agitated liquid-liquid microextraction using a solidifiable organic solvent followed by gas chromatography for analysis of amitriptyline and imipramine in human plasma and wastewater samples

A rapid and low-toxic microextraction method, namely air-agitated liquid-liquid microextraction (AALLME), was applied for the extraction of amitriptyline and imipramine from the human plasma and wastewater samples by solidification of the floating organic solvent droplets (SFO). Using very simple tools, the analytes contained in 10.0mL of an aqueous sample solution were simply extracted into the solidifiable organic solvent 1-dodecanol. For this purpose, in the absence of an organic disperser solvent, a mixture of the aqueous sample solution and the extraction solvent was repeatedly aspirated and dispensed using a syringe, and by enlarging the surface area between the donor and acceptor phases, a fast and efficient extraction was achieved. The response surface methodology (RSM) was used to optimize the experimental parameters involved. 14.0μL of the organic solvent used, a pH value of 12.0, 7.52% (w/v) salt addition, and 13 air-agitation cycles for the extraction number were found to be the optimal extraction conditions. Under the optimized experimental conditions, AALLME-SFO-GC-FID provided a good linearity in the range of 15–2000ngmL−1, low limits of detection (5.0–7.0ngmL−1), good extraction repeatabilities (relative standard deviations below 8.4%, n=5), and enrichment factors (EFs) of 682–731. In order to verify the performance of the method, the extraction efficiencies of the method based on the solidifiable organic solvent and the conventional AALLME method based on halogenated solvents were compared.

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

Recent 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. Intracerebral 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. Pretreatment 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. The 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.

Quantitative determination of imipramine and desipramine in human blood plasma by direct densitometry of thin-layer chromatograms.

Abstract Imipramine and desipramine have been estimated in the plasma of patients receiving therapeutic doses of imipramine. The compounds were extracted as bases into n-heptane, separated by thin-layer chromatography and transferred into coloured spots by an oxidative procedure. The quantification was made with a new densitometric technique of high sensitivity. The coefficient of variation was 11–16% at concentrations of 20 μg litre−1 (71ṁ2 nmol and 75ṁ0 nmol litre−1 for imipramine and desipramine respectively) and the recovery was 70–81%.

Optimizing the extraction, separation and quantification of tricyclic antidepressant drugs in human plasma with CE‐ESI‐TOF‐MS using cationic‐coated capillaries

In this study, the extraction and CE-ESI-TOF-MS analysis of tricyclic antidepressant (TCA) drugs imipramine, desipramine, clomipramine and norclomipramine in human plasma has been optimized. The CE capillaries were modified with ω-iodo-alkyl ammonium salt (M7C4I coating) to reduce analyte adsorption to the silica wall. The use of a strong cation exchange (SCX) solid-phase extraction (SPE) column specifically designed for the extraction of basic drug species from biofluids gave very clean extracts with high and reproducible recoveries. The extraction recoveries were ranging between 87 and 91% with % RSD values of 0.5-1.7% (n=3). The obtained strong cation exchange-SPE extracts of the TCA in human plasma only contained the analytes of interest. The optimized CE separation conditions were obtained by adding ACN and acetic acid to the sample while using an aqueous BGE. The CE-ESI-TOF-MS analysis was performed within 6 min for all TCA analytes under the optimized condition with peak efficiencies up to 1.4 x 10⁵ plates/m and an average % RSD of the migration times of the analytes of 0.3% (n=5). The presented method can readily be used for the extraction and quantification of basic drug species in human biological fluids and in pharmaceutical formulations.

Combining poly (methacrylic acid‐co‐ethylene glycol dimethacrylate) monolith microextraction and octadecyl phosphonic acid‐modified zirconia‐coated CEC with field‐enhanced sample injection for analysis of antidepressants in human plasma and urine

A method based on poly (methacrylic acid-co-ethylene glycol dimethacrylate) monolith microextraction and octadecylphosphonic acid-modified zirconia-coated CEC followed by field-enhanced sample injection preconcentration technique was proposed for sensitive CE-UV analysis of six antidepressants (doxepin, clozapine, imipramine, paroxetine, fluoxetine and chlorimipramine) in human plasma and urine. A poly(methacrylic acid-co-ethylene glycol dimethacrylate) monolithic capillary column was introduced for the extraction of antidepressants from urine and plasma samples. The hydrophobic main chains and acidic pendant groups of the monolithic column make it a superior material for extraction of basic analytes from aqueous matrix. After extraction, the desorption solvent, which normally provided an excellent medium to ensure direct compatibility for field-enhanced sample injection in CE, was analyzed by CE directly. By the use of alkylphosphonate-modified zirconia-coated CEC for separation of the basic compounds of antidepressants, high separation efficiency and resolution were achieved because that both hydrophobic interaction between analytes and alkylphosphonate-modified zirconia coat and electrophoretic effect work on the separation of antidepressants. The best separation was achieved using a buffer composed of 0.3 M ammonium acetate (adjusted to pH 4.5 with 1 M acetic acid) and 35% ACN v/v, with a temperature and voltage of 20 degrees C and 20 kV, respectively. By applying both preconcentration procedures, LODs of 11.4-51.5 and 3.7-17.0 microg/L were achieved for the six antidepressants in human plasma and urine, respectively. Excellent method of reproducibility was found over a linear range of 50-5000 microg/L in plasma and urine sample.

The CYP2C19*17 genotype is associated with lower imipramine plasma concentrations in a large group of depressed patients

CYP2C19 converts the tricyclic antidepressant imipramine to its active metabolite desipramine, which is subsequently inactivated by CYP2D6. The novel CYP2C19*17 allele causes ultrarapid metabolism of CYP2C19 substrates. We genotyped 178 depressed patients on imipramine for CYP2C19*17, and measured steady-state imipramine and desipramine plasma concentrations. Mean dose-corrected imipramine plasma concentration was significantly dependent on CYP2C19 genotype (Kruskal-Wallis test, P=0.01), with circa 30% lower levels in CYP2C19*17/*17 individuals compared with CYP2C19*1/*1 (wild-type) patients. The mean dose-corrected imipramine+desipramine plasma concentrations and imipramine/desipramine ratios were not significantly different between genotype subgroups (Kruskal-Wallis tests, P>or=0.12). In a multivariate analysis, we found a significant, but limited effect (P=0.035, eta(2)=0.031) of the CYP2C19*17 genotype on imipramine+desipramine concentrations. Although the CYP2C19*17 allele is associated with a significantly increased metabolism of imipramine, CYP2C19*17 genotyping will, in our view, not importantly contribute to dose management of patients on imipramine therapy guided by imipramine+desipramine plasma concentrations.

Flow Injection Chemiluminescence Determination of Imipramine in Tablets, Human Plasma and Urine Samples Based upon Oxidation with Singlet Oxygen Generated in N-Bromosuccinimide-Hydrogen Peroxide Reaction

Singlet oxygen generated in a reaction between N-bromosuccinimide and hydrogen peroxide was used for the chemiluminescence oxidation of imipramine. A strong chemiluminescence signal was observed when imipramine was mixed with N-bromosuccinimide and hydrogen peroxide under an alkaline condition. The chemiluminescence signal was linearly dependent on the concentration of imipramine in the range of 0.01 - 1.0 mg/L. The detection limit was 0.005 mg/L imipramine and the relative standard deviation was 1.5% for a 0.4 mg/L imipramine solution in 11 repeated measurements. The proposed method was successfully applied to the determination of imipramine in tablets, human plasma and urine samples.

Solid-phase extraction and analysis of 20 antidepressant drugs in human plasma by LC/MS with SSI method

A simultaneous determination of 20 antidepressant drugs (imipramine, amitriptyline, desipramine, trimipramine, nortriptyline, clomipramine, amoxapine, lofepramine, dosulepin, maprotiline, mianserin, setiptiline, trazodone, fluvoxamine, paroxetine, milnacipran, sulpiride, tandspirone, methylphenidate and melitracen) in human plasma was developed using LC/MS with sonic spray ionization (SSI) method. These drugs showed good separation and sensitivity by LC–MS using an Inertsil C-8 column with methanol:10 mM ammonium acetate (pH 5.0):acetonitrile (70:20:10) as mobile phase at 0.10 mL/min at 35 °C. Solid-phase extraction of these drugs added to the human plasma was performed with an Oasis ® HLB cartridge column. Recovery and limit of detection of these drugs were between 69 and 102% and between 0.03 and 0.63 μg/mL, respectively. The present procedure offers an easier and more convenient screening method for antidepressants, and will be useful for forensic toxicology investigations.

Alpha-1-acid glycoprotein in major depressive disorder: Relationships to severity, response to treatment and imipramine plasma levels

Background: Increased plasma levels of alpha-1-acid glycoprotein (AGP) were reported in major depressive disorder. However, the relationship between AGP levels, severity of depression, treatment response and antidepressant levels are still unclear. Methods: Plasma AGP levels were measured in 36 subjects with major depressive disorder before and after a 6-week treatment with imipramine and in 30 controls. Free imipramine plasma levels of depressed patients were measured at 6 weeks. Comparative analysis between depressed patients and controls, between non-responders ( N=12) and responders ( N=24), and between severely depressed patients ( N=14) and moderately depressed patients ( N=22) were made. Results: Depressed patients had significantly higher mean values of AGP than control subjects. Imipramine non-responders and specially severely depressed patients had significantly greater increases of AGP levels during treatment than other depressed subgroups. There was no correlation between baseline AGP levels and severity of depression or free imipramine levels. Limitations: The most significant limitations of this study are the small sample size and the fact that all the subjects were out-patients. Results should not be generalized to in-patient populations. Conclusions: Depressed patients showed high baseline concentrations of AGP. AGP levels did not predict either free imipramine plasma levels or differential response after 6 weeks of treatment with imipramine. A greater increase of AGP during treatment was associated with severity of depression and treatment non-response. Clinical implications: The relationship between high plasma levels of AGP, severity of depression and lack of treatment response is clarified. The influence of imipramine levels is minimized.

Highly selective and sensitive determination of tricyclic antidepressants in human plasma using high-performance liquid chromatography with post-column tris(2,2′-bipyridyl) ruthenium(III) chemiluminescence detection

A simple, selective and sensitive determination method of tricyclic antidepressants (imipramine, desipramine, amitriptyline, nortriptyline and clomipramine) has been developed using high-performance liquid chromatography (HPLC) with chemiluminescence detection. The method is based on the detection of aliphatic secondary or tertiary amino moieties in antidepressants with post-column tris(2,2′-bipyridyl)ruthenium(III) chemiluminescence. Five antidepressants were separated on a trimethylsilyl (TMS) column using a mixture of 50 mM phosphate buffer (pH 7.0) and acetonitrile (55:45, v/v) as a mobile phase. The eluate was on-line mixed with acidic tris(2,2′-bipyridyl)ruthenium(III) solution and the generated chemiluminescence was detected. The detection limits (signal-to-noise ratio=3) for antidepressants examined were 3.2–33.1 pg (12–105 fmol), for an injection volume of 20 μl. This HPLC system could sensitively detect other tri- or tetracyclic antidepressants and was successfully applied to the determination of imipramine and amitriptyline in human plasma after purification by two-step liquid–liquid extraction.

Alpha-1-acid glycoprotein in major depressive disorder

Abstract Background: Increased plasma levels of alpha-1-acid glycoprotein (AGP) were reported in major depressive disorder. However, the relationship between AGP levels, severity of depression, treatment response and antidepressant levels are still unclear. Methods: Plasma AGP levels were measured in 36 subjects with major depressive disorder before and after a 6-week treatment with imipramine and in 30 controls. Free imipramine plasma levels of depressed patients were measured at 6 weeks. Comparative analysis between depressed patients and controls, between non-responders ( N =12) and responders ( N =24), and between severely depressed patients ( N =14) and moderately depressed patients ( N =22) were made. Results: Depressed patients had significantly higher mean values of AGP than control subjects. Imipramine non-responders and specially severely depressed patients had significantly greater increases of AGP levels during treatment than other depressed subgroups. There was no correlation between baseline AGP levels and severity of depression or free imipramine levels. Limitations: The most significant limitations of this study are the small sample size and the fact that all the subjects were out-patients. Results should not be generalized to in-patient populations. Conclusions: Depressed patients showed high baseline concentrations of AGP. AGP levels did not predict either free imipramine plasma levels or differential response after 6 weeks of treatment with imipramine. A greater increase of AGP during treatment was associated with severity of depression and treatment non-response. Clinical implications: The relationship between high plasma levels of AGP, severity of depression and lack of treatment response is clarified. The influence of imipramine levels is minimized.

Quantitative Determination of Tricyclic Antidepressants and Their Metabolites in Plasma by Solid-Phase Extraction (Bond-Elut TCA) and Separation by Capillary Gas Chromatography With Nitrogen-Phosphorous Detection

An analytical method for the simultaneous determination of amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, and desmethylclomipramine in human plasma using promazine as internal standard is described. The method is based on a solid-phase extraction procedure using the Bond-Elut TCA columns followed by separation and detection using capillary gas chromatography with a specific nitrogen phosphorous detector (GC/NPD). Using the new extraction procedure, the problem of adsorption losses was overcome, and good recoveries were achieved for all compounds tested (>87%). Furthermore, clean extracts free of chromatographic interferences were obtained. Complete separation of underivatized, tricyclic antidepressant compounds was achieved in <11 minutes with reliable chromatographic performance. The limits of detection ranged from 1.2 to 5.8 microg/l. Calibration curves, showing good linearity, were prepared covering the therapeutic concentrations range expected (20 to 500 microg/l). The interassay precision values (RSD) ranged from 4.5% to 9.8%. It is concluded that extraction of amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, and desmethylclomipramine, with Bond Elut TCA solid-phase columns followed by their detection using GC/NPD provides a sensitive and reproducible method that can be easily automated for immediate and routine analysis of clinical samples.

20] Imipramine: A model drug for P450 research

Publisher Summary This chapter focuses on a model drug for P450 research, that is, imipramine. Imipramine is the prototype of the class of tricyclic antidepressants. The drug is eliminated by oxidation catalyzed by the cytochrome P450 system in the liver. The major oxidative pathways are N-demethylation in the side chain to the active metabolite desipramine and aromatic hydroxylation to 2-hydroxyimipramine. Desipramine is eliminated by 2-hydroxylation and by further N-demethylation to didesmethylimipramine and by 10-hydroxylation. With the development of an applicable thin-layer chromatography (TLC) method for the quantitative assessment of imipramine and desipramine in plasma it became possible to establish the basic pharmacokinetics of imipramine. The microsomal HPLC method was developed to use the 2-hydroxylation of imipramine as a marker reaction for CYP2D6 in vitro. The chapter gives an account of the high-performance liquid chromatography (HPLC) methods used for the assay of imipramine and its metabolites in plasma, urine, and human liver microsome preparations.

Simultaneous HPLC analysis of tricyclic antidepressants and metabolites in plasma samples

A sensitive, selective and rapid reverse-phase high-performance liquid Chromatographic method was developed for the simultaneous analysis of imipramine, desipramine, amitriptyline and nortriptyline in human plasma. The procedure consisted of extracting the drugs and the internal standard (clomipramine) from 1 ml plasma with hexane:isoamyl alcohol (99:1, v/v) in alkaline medium. A newly marketed column, LiChrospher® 60 RP-select B (dp 5 μm) of Merck was employed. The mobile phase, consisting of acetonitrile/0.25 N sodium acetate buffer at pH 5.5 (50:50, v/v), was delivered at a flow rate of 1.0 ml/min, and detection at 254 nm. The precision, linearity and limit of quantification of the method were within acceptable limits. The method was considered adequate and has, therefore, been used in routine analysis for the therapeutic control of depressed patients.

Decreased plasma concentrations of imipramine and desipramine following cholestyramine intake in depressed patients.

The effect of cholestyramine (4 g t.i.d. for 5 days) on the steady-state plasma concentrations of imipramine and desipramine was assessed in six depressed patients receiving chronic treatment with imipramine (75-150 mg/day). Compared with baseline, cholestyramine treatment was associated with an average 23% decrease in plasma imipramine levels [from 211 +/- 95 to 159 +/- 67 nmol/L, (mean +/- SD), p < 0.05], whereas desipramine levels decreased only marginally. These data suggest that administration of cholestyramine at therapeutic doses impairs the gastrointestinal absorption of concurrently prescribed imipramine by an extent that is potentially clinically significant.

Imipramine plasma concentrations and response in panic disorder

Imipramine plasma concentrations and response in panic disorder

Sensitive Determination in Plasma of Imipramine and Desipramine by High Performance Liquid Chromatography Using Electrochemical Detection

Abstract A sensitive high-performance liquid chromatographic method, using electrochemical detection, has been developed for the analysis of both imipramine and desipramine in plasma. This involved many n-hexane-isoamyl alcohol extractions, in the presence of an internal standard (trimipramine). Analysis was performed by isocratic elution with 27 % 0.01M potassium dihydrogen phosphate, 40 % acetonitrile, 33 % methanol, with the pH adjusted to 9, on a Nucleosil 5 μm, CN column, with electrochemical detection at + 0.9 Volt. The limit of sensitivity of the assay was 1.0 ng/ml. The method was applied to a single dose (7 5 mg) pharmacokinetic study of imipramine, in healthy volunteers, with a good accuracy (95-105 %) and precision (less than 11.5 %).

Imipramine in panic disorder. 1. Clinical response and pharmacological changes

Clinical and biochemical variables were monitored in 18 patients with panic disorder before and during treatment with imipramine over 16 weeks. Imipramine dosage was slowly increased from a starting dose of 10 mg daily, to prevent early treatment drop-outs. All patients were effectively treated for at least 6 weeks, and only two patients dropped out before the end of the study. There were substantial reductions in panic attack frequency, ratings of depression and avoidance behaviour, but only small reductions in ratings of state and general anxiety. Plasma levels of the noradrenaline metabolite 3-methoxy-4-hydroxyphenyl- ethylene glycol initially fell after starting imipramine, but returned to pre-treatment levels by week 8 of treatment. Plasma imipramine and/or desipramine concentrations were very variable and did not correlate with either psychological or biochemical changes during treatment.