Plasma Concentrations Of Imipramine 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.

Time of Administration of Acute or Chronic Doses of Imipramine Affects its Antidepressant Action in Rats.

The pathogenesis and therapeutics of depression are linked to the operation of the circadian system. Here, we studied the chronopharmacological action of a tricyclic antidepressant, imipramine. Male adult Wistar–Hannover rats were administered imipramine acutely or chronically in the morning or in the evening. The antidepressant action of imipramine was analyzed using the forced swim test (FST). A single dose of imipramine (30 mg/kg) in the morning, but not in the evening, reduced immobility and increased climbing in the FST. The plasma concentrations of imipramine and its metabolite, desipramine, were slightly higher in the morning than in the evening, which might explain the dosing time-dependent action of imipramine. Next, we analyzed the effect of chronic imipramine treatment. Rats received imipramine in the morning or in the evening for 2 weeks. The morning treatment resulted in larger effects in the FST than the evening treatment, and was effective at a dose that was ineffective when administered acutely. The levels of brain α-adrenergic receptors tended to decrease after chronic imipramine treatment. Imipramine might interact with noradrenergic neurons, and this interaction might chronically alter receptor expression. This alteration seemed greater in the morning than in the evening, which might explain the dosing time-dependent action of imipramine.

Comparative bioavailability study of oral formulations of imipramine tablets in healthy volunteers

BackgroundPlasma levels of imipramine vary widely between individuals. They are probably due to genetic polymorphism and inter-individual differences in the metabolism of imipramine.PurposeThe objective of this study was to obtain...

In Vivo Canine Model Comparison of Cardiovascular Effects of Antidepressants Milnacipran and Imipramine

Milnacipran is a specific serotonin and norepinephrine reuptake inhibitor, which has been widely used against major depressive episodes. In this study, cardiovascular effects of milnacipran were assessed in comparison with those of a typical tricyclic antidepressant imipramine using the halothane-anesthetized dogs. Milnacipran (n=6) or imipramine (n=6) was intravenously administrated in three escalating doses of 0.1, 1 and 10mg/kg over 10min with a pause of 20min between the doses. Clinically relevant plasma concentrations were obtained after 0.1-1mg/kg of milnacipran in this study, whereas therapeutic dose and plasma concentration of imipramine were reported to be similar to those of milnacipran. The low and middle doses of milnacipran hardly affected cardiohemodynamic or electrophysiological variables except that they slightly increased vascular tone and ventricular contraction, whereas same doses of imipramine delayed repolarization process without affecting the other variables. The high dose of both milnacipran and imipramine induced similar extent of negative chronotropic, inotropic and dromotropic effects together with vasoconstriction and repolarization delay. Thus, the effects of milnacipran may be more selective for cardiohemodynamics than for repolarization delay, whereas reverse will be true for imipramine, supporting lack of clinical report of patients with milnacipran-induced long QT syndrome unlike imipramine.

Imipramine plasma concentrations and response in panic disorder

Imipramine plasma concentrations and response in panic disorder

Increased plasma concentration of imipramine following augmentation with fluvoxamine

Increased plasma concentration of imipramine following augmentation with fluvoxamine

Effect of buspirone or fluvoxamine on plasma concentrations of imipramine and desipramine in depressed patients

Effect of buspirone or fluvoxamine on plasma concentrations of imipramine and desipramine in depressed patients

Chronopharmacokinetics of Imipramine and Desipramine in Rat Forebrain and Plasma After Single and Chronic Treatment with Imipramine

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.

Urinary desipramine hydroxylation index and steady-state plasma concentrations of imipramine and desipramine.

An index of desipramine (DMI) hydroxylation, calculated as the ratio between the amounts of DMI and 2-hydroxydesipramine (2-OH-DMI) excreted in urine after 25 mg orally, was determined in 16 depressed patients. The index varied almost 100-fold between the patients and correlated significantly to the steady-state plasma concentrations of DMI (rs = 0.85; p less than 0.01) but not to the plasma levels of imipramine (IMI) when the patients were treated with 75 mg of IMI daily. Eleven of the 16 patients were subsequently treated with DMI and a significant relationship was again found between the plasma levels of DMI and the urinary DMI-hydroxylation index (rs = 0.87; p less than 0.01). The latter may be utilized in therapeutic drug monitoring to identify individuals with unusually rapid or slow hydroxylation of DMI.

Effects of Combined Administration of Diazepam and Imipramine Hydrochloride in Rats

The effects of daily oral administration of imipramine hydrochloride (5-[3-(dimethylamino)propyl]-10, 11 -dihydro-5H-dibenz-[b,f]azepine monohydrochloride; 50mg/kg) and/or diazepam (7-chloro-1, 3-dihydro-1 -methyl-5-phenyl-2H-1, 4-benzodiazepin-2-one; 5mg/kg) in a 1% aqueous solution of carboxymethylcellulose sodium salt (CMC) on the body weight, organ weights, and activities of various enzymes, including drug metabolizing enzyme systems were investigated in rats during a 15-day period. The plasma concentrations of imipramine and desipramine were also determined. In addition, the effect of a single intravenous administration of imipramine hydrochloride (5mg/kg) on the plasma concentration-time profiles of imipramine and desipramine was investigated in rats given the same drug treatments. The plasma concentration-time profiles of imipramine and desipramine were analyzed pharmacokinetically. The rats treated with imipramine hydrochloride showed a greater inhibition of body weight gain than those treated with diazepam, and those treated with imipramine hydrochloride and diazepam simultaneously showed a body weight gain similar to those treated with imipramine hydrochloride alone. No significant differences in organ weight (per 100g of body weight) were found. The imipramine hydrochloride plus diazepam treatment group showed a greater increase in drug-metabolizing enzyme activities than the imipramine hydrochloride treatment group, but the difference was not statistically significant. However, the plasma levels of imipramine and desipramine after oral administration for 15 d suggested that the imipramine hydro-chloride plus diazepam treatment group did show increased imipramine metabolism. Single intravenous administration of imipramine hydrochloride caused a reduction in the first-order elimination rate constant (kel) in the imipramine hydrochloride treatment group, and reductions of the first-order distribution rate constants (k12, k21) and kel in the imipramine hydrochloride plus diazepam treatment group. In terms of the area under the concentration-time curve (AUC) of desipramine after intravenous administration of imipramine hydrochloride (5mg/kg), there was no significant difference between the imipramine hydrochloride treatment group and the imipramine hydrochloride plus diazepam treatment group. Plasma desipramine was not detectable after intravenous administration of imipramine hydrochloride (5mg/kg) to the control group. The results indicate that daily oral administration of imipramine hydrochloride enhances the metabolism of imipramine and may induce changes of distribution and excretion of imipramine and desipramine. The effects appear to be greater in the case of coadministration of imipramine hydrochloride and diazepam.

Targeting imipramine dose in children with depression.

The response to imipramine (IMI) in children with depression has been shown to correlate with total levels of IMI plus its active metabolite desmethylimipramine (DMI). The pharmacokinetics of IMI + DMI in children with depression are examined, and the single-point prediction of steady-state IMI + DMI levels at minimum therapeutic concentrations for prepubertal depression is proposed. With a single, 25 mg oral dose of IMI, a plasma concentration of IMI + DMI 24 hours after dosing correlates (r = 0.92) with steady-state IMI + DMI levels in children with depression receiving 3 mg/kg/day IMI. The targeting of IMI dose in the child population with depression to rapidly achieve a minimum therapeutic concentration is shown to be feasible and reliable within theoretic limits.

Antidepressant treatment of children: clinical relapse is unrelated to tricyclic plasma concentrations.

Plasma concentrations of imipramine and amitriptyline and their desmethylated metabolites were measured in 20 children being treated for major depressive illness 2 wk. and 5 to 10 wk. after achieving drug dosages of 2.25 mg/kg body weight. At 2 wk. all children had exhibited clinical improvement, but by 10 wk. 4 of the 10 children treated with imipramine and 5 of the 10 children treated with amitriptyline had experienced clinical relapse of depressive symptoms. Tricyclic antidepressant plasma concentrations and ratios were comparable in the subgroups of children who maintained their clinical improvement and those who relapsed. There was no evidence of a systematic decline in plasma tricyclic antidepressant concentrations in those children who relapsed.

Plasma Concentrations of Imipramine and Clinical Response Among Depressed Outpatients

Plasma Concentrations of Imipramine and Clinical Response Among Depressed Outpatients

The electrocardiographic and antiarrhythmic effects of imipramine hydrochloride at therapeutic plasma concentrations.

The electrocardiographic effects of imipramine hydrochloride at therapeutic plasma concentrations were determined in 44 depressed patients during a 6-week clinical outcome study of depression. During each week of the protocol, i.e., 2 weeks of control and 4 weeks of drug treatment, a standard 12-lead ECG, high-speed, high-fidelity ECG tracings, and a 24-hour continuous ECG recording were obtained. PR, QRS, and QTc intervals, T-wave amplitude, heart rate and frequency of ventricular premature depolarizations (VPDs) were measured. The plasma concentration of imipramine and desmethylimipramine was measured three times a week. Imipramine prolonged the PR (p less than 0.001), QRS (p less than 0.001) and QTc (p less than 0.001) intervals, increased the heart rate (p less than 0.001) and lowered T-wave amplitude (p less than 0.05) during the 4 weeks of treatment. No patient developed high-grade atrioventricular block or severe intraventricular conduction abnormalities. In addition, imipramine had a potent antiarrhythmic action in patients who were recovering from depression. Ten of 11 patients who had more than 10 VPDs/hour had 90% or greater arrhythmia suppression during antidepressant treatment with imipramine at plasma concentrations ranging from 100--302 ng/ml.

Steady-state kinetics of imipramine in patients

Steady-state plasma level kinetics were studied in 76 patients given imipramine (IP) 150 to 225 mg/day for 2–5 weeks. IP was given in three divided doses at 8.00 a.m., 1.00 p.m. and 5.00 p.m. Plasma concentrations of IP and its active metabolite desipramine (DMI) were determined by quantitative in situ thin-layer chromatography. The plasma levels of IP and DMI showed pronounced flucutations throughout the day with a ratio of about 2 between highest and lowest level. Patients with steady-state levels of IP and/or DMI below 50 μg/l reached this within 1 week of treatment. Patients with higher steady-state levels reached steady-state concentrations within 2–3 weeks. There were some intraindividual fluctuations in plasma levels from week to week after steady state had been reached (coefficient of variation: 10–20%). Interindividually, the steady-state levels corrected to a dose of 3.5 mg/kg per day varied considerably: IP: 6–356 μg/l, DMI: 24–659 μg/l and IP+DMI: 58–809 μg/l. The steady-state plasma levels showed a skew distribution that became normal by logarithmic transformation. The IP/DMI ratio ranged from 0.07 to 5.5 with a median value of 0.47. Compared to data from amitriptyline treated patients the IP/DMI ratios had significantly lower median value and larger variation than the corresponding plasma level ratios of amitriptyline/nortriptyline. Several statistically significant differences in steady-state levels between age groups were found. For IP: Women aged 30–39 had lower levels than women aged 20–29, 40–49, and 50–59, and men aged 50–59 and 60–65; men aged 30–39 had lower levels than men aged 60–65. For DMI: Women aged 30–39 had lower levels than women aged 50–59.

The electroencephalographic and psychological effects of imipramine in depressed inpatients.

Ten patients with psychotic depression were assessed on a battery of clinical, EEG, psychological, and biochemical measures during treatment with imipramine (150 mg/day). Significant changes occurred in the scores on self-rated and observer-rated depression scales and on an observer-rated side effect scale. Significant changes also occurred in the EEG evoked response, but the effects on spontaneous activity were minimal. The psychological measures revealed an improvement in performance as treatment progressed. The clinical significance of the changes observed was assessed with reference to their correlations with the clinical rating scores and with the plasma concentrations of imipramine and desmethylimipramine, and the changes observed following the administration of imipramine to non-depressed normal subjects. Changes in evoked EEG activity seemed on balance to be direct central effects of imipramine, whereas changes in psychological performance appeared to be secondary to clinical change.

Plasma levels of imipramine and desmethylimipramine and antidepressant effect during controlled therapy(author's transl)

24 depressed impatients received a standardized treatment by imipramine, 6 among them receiving also levomepromazine. Plasma concentration of imipramine and DMI were controlled weekly during the study, and standardized assessment of clinical state were made by a psychiatrist who was unware of biochemical findings. Interaction between the antidepressant and neuroleptic metabolism is shown by a significant increase of DMI levels, though the clinical effect of the drug association could not be asserted. The therapeutic effect seems mainly dependant of etiology of depression. Endogeneous depressions improve more than other types. Among endogenous depressions a significant correlation was found between the degree of clinical improvement after three weeks and DMI level, sum of imipramine + DMI level, but not with concentration of imipramine alone.