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Inhibition of binedaline binding to human alpha 1-acid glycoprotein and other serum proteins by chlorpromazine, imipramine, and propranolol.

Binedaline (1-[[2-(dimethylamino)ethyl]methylamino]- 3-phenylindole) binding to human alpha 1-acid glycoprotein and other serum proteins was studied in the presence of three basic compounds: chlorpromazine, propranolol, and imipramine. In serum, at therapeutic concentrations, binedaline binding was not modified by the presence of these three compounds, nor did binedaline inhibit the binding of these compounds. With isolated alpha 1-acid glycoprotein, the four drugs exhibited competitive inhibition indicating that they share a common binding site on this protein.

Adult↗

Stable isotope coadministration methodology for the estimation of the fraction of imipramine metabolized to desipramine.

The application of a stable isotope coadministration technique for estimating the fraction (fm) of imipramine (IP) that is converted to desipramine (DMI) is described. Four healthy male subjects received 25 mg of IP-d4 hydrochloride orally with 25 mg of DMI hydrochloride. The plasma concentrations of IP-d4, DMI-d4, and DMI were determined by capillary gas chromatography-mass spectrometry-selected ion monitoring using d8 analogues as internal standards. The fm values, calculated from the ratio of the area under the plasma concentration-time curve of DMI-d4 to that of DMI, varied from 0.54 to 0.85.

Adult↗

Effect of prenatal imipramine exposure on development of the postnatal rat heart and brain.

Imipramine (IMI) was administered s.c. at 0, 5, or 10 mg/kg/day to pregnant rats on gestation days 8-20 to assess possible alterations in postnatal heart and brain development. Maternal weight gain was significantly reduced in a dose-response manner, but litter size and pup weight on postnatal day (PND) 1 were unaffected. On PND 1, litters were culled to 10 pups for analysis on PNDs 4/5, 7/8, 14/15, and 21/22. Pup body weight was not affected at any age measured, but heart weight was significantly reduced at 10 mg/kg IMI on PNDs 4/5 and 7/8. Brain weight was increased in a dose-related pattern on PNDs 4/5 and 7/8 and was significantly higher at 5 mg/kg IMI on PND 14/15. No significant effect was observed in heart or brain protein and DNA content or in cardiac beta-adrenergic receptor concentration. Prenatal IMI exposure had no effect on basal cardiac ornithine decarboxylase (ODC), an enzyme associated with growth and development, but basal brain ODC was lower at 5 mg/kg IMI at all ages measured. Cardiac ODC stimulation by insulin was unaffected by prenatal exposure to IMI, but isoproterenol-stimulated ODC was increased on PND 21/22 at 5 mg/kg IMI. In conclusion, the IMI-related changes in several parameters suggest that when maternal IMI treatment is used, alterations in postnatal heart and brain development must be considered as possible outcomes.

Aging↗

Teratologic evaluation of imipramine hydrochloride in bonnet (Macaca radiata) and rhesus monkeys (Macaca mulatta).

Imipramine hydrochloride was administered orally twice daily to 18 bonnet and 3 rhesus monkeys between days 23 and 45 of pregnancy for 1-3 or 18-22 days at 1, 2, and 10 times the recommended human dose. No teratologic changes were observed, although signs of maternal toxicity occurred at the high dose level, and the abortion rate was higher than in controls.

Abortifacient Agents↗

Imipramine inhibits Cl(-) secretion by desensitization of beta-adrenergic receptors in calu-3 human airway cells.

Recent investigations have found that tetracyclic antidepressants like imipramine (IMP) have high-affinity sites not only in brain but also in mammalian lung. In the present study, we examined the effects of IMP on the Cl(-) secretion produced by isoproterenol (ISP), a beta-adrenergic receptor (beta-AR) agonist, in Calu-3 human airway cells. ISP applied in the basolateral solution generated a sustained short-circuit current that was abolished by diphenylamine-2-carboxylate, a Cl(-) channel blocker. IMP (0.01-1 mM) applied in the apical or basolateral solution for 30 min significantly inhibited the ISP-induced responses in a concentration-dependent manner, and the inhibitory effects of this drug were remarkable when applied from the apical rather than the basolateral side. ISP-induced responses were mimicked by forskolin- and 8-bromo-cyclic AMP-induced ones, but which were insensitive to IMP. These results indicate that IMP desensitizes the beta-AR on the basolateral membrane from the cytosolic side in Calu-3 cells.

Adrenergic Uptake Inhibitors↗

Surfactant effects of chlorpromazine and imipramine on lipid bilayers containing sphingomyelin and cholesterol.

The surface-active drugs chlorpromazine (CPZ) and imipramine (IP) have been tested on large unilamellar vesicles composed of phosphatidylcholine (PC), sphingomyelin (SM), and cholesterol (Ch) in different proportions. The well-characterized nonionic detergent Triton X-100 (TX) has also been used in parallel experiments. Leakage of vesicular aqueous contents and bilayer solubilization have been measured for each surfactant molecule and vesicle composition. All three surface-active molecules behave in a qualitatively similar way, irrespective of bilayer composition: they induce leakage at concentrations well below their critical micellar concentrations (cmc) and solubilization near the cmc. In these events, the potency of the three surfactants under study increases with decreasing cmc, in the order IP<CPZ<TX. With all three surfactant molecules, addition of SM to PC bilayers made the vesicles more sensitive to the detergents. The three surfactants had the same effects on PC : SM (3 : 1 mole ratio) and on PC : SM : Ch (3 : 1 : 1 mole ratio) vesicles when leakage was tested. However, the presence of cholesterol made the bilayers more resistant to solubilization. In the presence of both SM and Ch, CPZ and IP, but not TX, were able to achieve complete bilayer solubilization. Since the outer monolayer of plasma membranes is rich in SM and Ch, the present data could be relevant in understanding some of the CPZ or IP effects at the membrane level.

Adrenergic Uptake Inhibitors↗

Inhibition of MAO activity, 3H-imipramine binding, 3H-paroxetine binding and 3H-5-HT uptake by human cerebrospinal fluid.

Addition of small amount of human cerebrospinal fluid (CSF) inhibited both types of MAO in monkey brain mitochondria. The specific binding of 3H-paroxetine decreased remarkably with increasing CSF volumes, while 3H-imipramine binding was slightly inhibited. Scatchard analysis of 3H-paroxetine binding in the presence and absence of CSF indicated that the inhibitory effect was associated with a decreased Bmax without an appreciable change in Kd. Addition of CSF induced an inhibition of uncompetitive 3H-5-HT uptake to monkey cerebral membranes. These results indicate that the materials in human CSF inhibit 3H-paroxetine binding, and modulate the uptake system for 5-HT.

Animals↗

Experimental anxiety and antidepressant drugs: the effects of moclobemide, a selective reversible MAO-A inhibitor, fluoxetine and imipramine in mice.

Available evidence derived from behavioural and clinical studies indicates that antidepressant drugs may be effective as anxiolytic agents. In this connection, the present study was designed to assess the behavioural effects of three antidepressant drugs, i.e. imipramine (IMI), a non selective serotonin (5-HT) and noradrenaline re-uptake (NA) inhibitor, fluoxetine (FLU), a selective 5-HT re-uptake inhibitor (SSRI) and moclobemide (MOC), a reversible inhibitor of type A monoamine-oxidase enzyme (RIMA) on anxiety, exploratory and locomotor activities in mice. The experiments used two animal models which attempt to separate these three factors: the "light-dark aversion" test and the "open-field" test. Naive female CD1 mice were administered intraperitoneally (i.p.) 30 min before testing with IMI (10, 20 and 40 mg/kg) or FLU (5, 10 and 20 mg/kg) or MOC (1, 5 and 10 mg/kg) or vehicle. Results showed that IMI (10 and 20 mg/kg), FLU (10 and 20 mg/kg) and MOC (1, 5 and 10 mg/kg) significantly reduced the aversive behavior of mice for the lit area in the light/dark aversion test, suggesting an anxiolytic-like effect. In fact, vehicle controls preferred the dark box where they spent approximately 70% of their time, indicating that light serves as an anxiogenic stimulus. Importantly, the anxiolytic-like effects of these antidepressant drugs were not associated with any increase in locomotor activity. In summary, these data suggest that FLU and the new generation of RIMA, exemplified by MOC, in terms of probable efficacy and greater safety, are of interest as treatment for a broad spectrum of anxiety disorders.

Analysis of Variance↗

Comparison of the metabolism of the three antidepressants amitriptyline, imipramine, and chlorimipramine in vitro in rat liver microsomes.

The metabolism of the tricyclic antidepressants amitriptyline (AMI), imipramine (IMI), chlorimipramine (CMI) and some of their metabolites was studied in vitro in isolated liver microsomes of female Spraque-Dawley rats. Nine metabolites of AMI, seven metabolites of IMI, and 11 metabolites of CMI were quantitatively determined with high-performance liquid chromatography. The main metabolic reactions, mediated by an NADPH generating system, were hydroxylation, demethylation, and N-oxidation. The ratio of these reactions was different for the three drugs. AMI was hydroxylated more than CMI and CMI more than IMI. The order for demethylation was CMI greater than AMI = IMI, the order for N-oxidation IMI greater than CMI less than or equal to AMI. The substrate dependence of metabolism was investigated. Demethylation and N-oxidation increased proportionally to increasing substrate concentrations, whereas formation of hydroxylated metabolites became saturated (in the concentration range of 10(-6)-10(-5) M). The in vitro metabolism was compared with the in vivo metabolism in humans, reflected by the plasma concentrations of these drugs and their metabolites. A good agreement in metabolic pathways was found.

Amitriptyline↗

Steady-state kinetics of doxepin and imipramine in Saudi patients with interethnic comparison.

The pharmacokinetics of doxepin (DX) was studied in 21 Saudi patients treated long term with oral doses of this tricyclic antidepressant agent. The mean (SEM) values of the dose-normalized steady-state concentration and the apparent clearance after oral administration of this drug were 25.8 (4.8) ng.ml-1/mg.kg-1 and 2.529 (0.342) 1.h-1.kg-1, respectively. The pharmacokinetics of imipramine (IMI) was also studied in 30 Saudi patients who received oral doses of this drug for long durations. The mean dose-normalized steady-state concentration of IMI was 68.3 (19.7) ng.ml-1/mg.kg-1, and the mean apparent clearance after oral administration of IMI was 1.619 (0.353) 1.h-1. kg-1. The mean (SEM) ratio of the steady-state concentration of the metabolite desipramine (DES) to that of IMI (DES/IMI) was 0.873 (0.151). Using this value and the ratio of the mean apparent clearance after oral administration (TCL) of DES to that of IMI, the fraction of IMI metabolized to DES was calculated to be 0.489. The TCL of DES was estimated from data obtained for three additional patients who received oral doses of this drug for long durations. A mean value of 0.907 (0.351) 1.h-1.kg-1 was obtained.

Adolescent↗

Platelet 3H-imipramine binding and steroid hormones serum concentrations during the menstrual cycle.

The presence of high affinity binding sites for 3H-imipramine (3H-IMI) in human platelets is by now well established. This recognition site is associated with the transporter for 5HT, and may be a biological marker in depression. Fluctuations of other putative biological markers of depression (i.e. platelet MAO activity) have been demonstrated and shown to be correlated with variations in steroid hormones. Therefore, the KD and Bmax of 3H-IMI binding was determined in platelets of young women during the menstrual cycle. Our results indicate that within the limits of intraindividual variations, neither the KD or the Bmax of 3H-IMI binding in platelets is significantly modified during the menstrual cycle.

Adult↗

Dopamine receptor binding in rat striatum: ultradian rhythm and its modification by chronic imipramine.

To investigate diurnal variations in dopamine receptor binding, the amount of specifically bound 3H-spiroperidol was measured at 4-h intervals over a 24-h period in the striatum of rats which had been housed under a controlled 12-h light-dark cycle (lights on 7 a.m.). A highly significant ultradian rhythm with peaks at 2 a.m. and 2 p.m. was found with an amplitude of about 75%. Chronic imipramine modified the rhythm such that the two peaks occurred 4 h later and amplitude as well as 24-h mean of binding decreased. Scatchard analysis at times of least and greatest binding indicated that the differences in binding were due not to changes in the affinity, but in the number of binding sites. These results are interpreted with regard to the mode of action of psychoactive drugs and to postulated changes of receptor sensitivity in neurological and psychiatric disorders.

Animals↗

Absolute bioavailability of imipramine: influence of food.

Imipramine hydrochloride (IMI) was administered to 12 healthy volunteers on three occasions in random sequence: 12.5 mg IV, 50 mg orally after overnight fast, and 50 mg orally 30 min after eating a standardized breakfast. IMI concentrations were measured by gas-liquid chromatography using nitrogen-phosphorous detection and pharmacokinetic and bioavailability parameters determined by iterative nonlinear least-squares regression analysis. After IV administration, mean kinetic variables were: volume of distribution, 21.0 l/kg; total clearance, 12.8 ml/min per kg, and elimination half-life, 21. h. Mean absolute bioavailability of IMI in the fasting state was 43.6%. When IMI was administered immediately after the standardized meal, absolute bioavailability was 44.1%. After oral administration, the time to peak IMI level was not changed by concurrent food ingestion (2.8 vs 3.2 h after dosage), and the peak IMI concentration was no different (35 vs 30 ng/ml). Thus concurrent food ingestion has no effect on IMI absolute bioavailability, peak concentration attained after oral dosage, or the time to peak concentration.

Administration, Oral↗

Cerebral and blood pharmacokinetics of imipramine and its active metabolites in the pregnant rat.

A single IP dose of imipramine (IMI) was administered to pregnant rats. Whole blood, plasma, and brain concentrations of IMI, desipramine (DMI), and their 2-hydroxylated metabolites were separated by high-pressure liquid chromatography and quantified by fluorescence detection. IMI and DMI rapidly appeared in brain tissue in concentrations greatly exceeding those in whole blood and plasma. The much higher concentration and longer persistence of DMI in brain compared to IMI suggests that the predominant central effects from administered IMI result from biotransformation to DMI. The metabolite: "parent" area under the curve ratios for the hydroxylated metabolites indicate that their contribution to the pharmacologic effects of IMI and DMI are probably negligible.

Animals↗

The analysis and disposition of imipramine and its active metabolites in man.

Single oral and intramuscular (i.m.) doses of imipramine (IMI) were administered to four normal males. Serum and urine concentrations of IMI, desipramine (DMI) and their unconjugated 2-hydroxy metabolites were measured by high-pressure liquid chromatography (HPLC). Urinary conjugated 2-hydroxy metabolites were also measured after enzyme hydrolysis. Computer analysis of serum concentration and urinary excretion rate data allowed confirmation of drug and metabolite kinetics, and calculation of pharmacokinetic parameters. The rapid appearance of the metabolites in serum indicates that sequential first-pass metabolism of IMI involves both hydroxylation and demethylation. However, the dose-normalized areas under the serum concentration-time curves indicate that the fractions of the doses converted to metabolites were similar after both routes of IMI administration. Similar total fractions of the i.m. and oral doses recovered in urine indicate complete absorption of the oral doses. Inclusion of the metabolites increased the apparent availability of active components after oral IMI from 22%-50% to 45%-94%. Both the 2-hydroxy metabolites exhibited formation rate-limited kinetics, whereas DMI kinetics were elimination rate-limited. The t1/2 of IMI and 2-hydroxyimipramine (2-OH-IMI) was 6-18 h, while that of DMI and 2- hydroxydesipramine (2-OH-DMI) was 12-36 h. The t1/2 of these compounds was 1.5-2 times longer after the i.m. doses. The metabolite/parent ratios and the disposition of the individual metabolites confirm findings that chronic dosing results in only limited accumulation of hydroxy metabolites.

Administration, Oral↗

Attenuation by electroshock treatment of the haloperidol-induced rise in the binding of 3H-imipramine to rat brain membranes.

Studies were conducted in rats to investigate whether chronic haloperidol treatment, electroshock treatment (EST), or a combination of both affects the high-affinity binding of 3H-imipramine to cerebral membranes. Chronic haloperidol (2 mg/kg SC daily for 28 days) resulted in a significant decrease in the density of binding sites in animals killed 1 h after the last treatment, but binding was markedly enhanced after a "washout" period of 5 days. In animals subjected to EST (20-30 mA, 1.5 s, 60 Hz; three times a week for 4 weeks) and killed 1 h after the last treatment, there were no apparent changes, but when animals were allowed a recovery period of 5 days there appeared to be a slight increase in binding. The marked increase in binding seen after haloperidol withdrawal was no longer apparent in animals treated with both haloperidol and EST, indicating that EST acts to attenuate the increase in binding seen after withdrawal of chronic haloperidol. It is suggested that chronic haloperidol may influence presynaptic recognition sites that regulate serotonin uptake and that EST may interact with haloperidol to "stabilize" these presynaptic sites.

Animals↗

Retroactive impairment of cooperative learning by imipramine and chlordiazepoxide in rats.

Pairs of rats were placed in an apparatus where their sole food source hung over an electrified grid. The current was shut off only while one rat remained on a platform out of reach of the food, thus allowing his partner to eat. Mastery of the process of taking turns at eating required about 10 daily sessions. Injection of imipramine or chlordiazepoxide a few minutes after each feeding session prevented the development of this cooperative behavior. Drug injection 3 hrs after each session had no effect. Suppression of REM sleep during the first 3 hrs after training was considered the most likely mechanism of the drug-induced impairment.

Animals↗

Binding of imipramine to plasma protein and to brain tissue: relationship to CSF tricyclic levels in man.

The possible clinical significance of the plasma protein binding of tricyclic antidepressants has been evaluated using imipramine (IMI), a typical tricyclic. Using equilibrium dialysis, the in vitro binding of IMI to plasma was compared to that of brain tissue. Cerebrospinal fluid (CSF) IMI was used as an independent measure of 'free' drug in the central nervous system. Intrinsic metabolic clearances were calculated on the basis of steady-state plasma IMI concentrations. There were three significant results: (1) variations in plasma binding are not great; (2) plasma protein binding does not limit the entry of IMI into the CSF; (3) variations in metabolism (intrinsic clearance) account for almost all variations in CSF concentrations of drug. It is concluded that measurement of free tricyclic antidepressant is not indicated in studies of clinical efficacy.

Animals↗