Imipramine (0.5-300 μM, 3 days) reduces the viability of HCT-116 cells [1]. Cell invasion (48 hours) and migration (7.5 hours) are inhibited by imipramine (20 μM) [1]. In U-87MG glioma cells, imipramine (50 μM, 0-240 min) suppresses the PI3K/Akt/mTOR signaling pathway [2]. In U-87MG glioma cells, imipramine (60 μM, 24 hours) promotes autophagy [2]. In HL-60 cells, imipramine (80 μM, 24 hours) causes apoptosis [3].

Imipramine (20 mg/kg intraperitoneally or 15 mg/kg orally; given daily for 24 days) attenuates neuroinflammatory signaling and reverses stress-induced social avoidance in mice [4].

Cell Viability Assay[1]
Cell Types: DLD-1, HCT-116 and SW-480
Tested Concentrations: 0.5-300 μM
Incubation Duration: 3 days
Experimental Results: Inhibition of cell viability, HCT-116 is more sensitive than DLD-1 and SW-480 .

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Cell migration assay[1]
Cell Types: SW-480, DLD-1 and HCT-116
Tested Concentrations: 20 μM
Incubation Duration: 7 hrs (hours)
Experimental Results: Significant migration inhibition was produced in all cell lines tested.

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Cell invasion experiment [1]
Cell Types: HCT-116
Tested Concentrations: 20 μM
Incubation Duration: 48 h
Experimental Results: Matrigel inhibits cell invasion.

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Western Blot Analysis[2]
Cell Types: U-87MG
Tested Concentrations: 50 μM
Incubation Duration: 0, 15, 30, 60, 120 and 240 minutes
Experimental Results: Significant time-dependent inhibition of phosphorylation of Akt (Ser473) and mTOR (Ser2481) The way. Also dephosphorylates p70 S6K, a downstream target of mTOR.

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Autophagy assay [2]
Cell Types: U-87MG
Tested Concentrations: 60 μM
Incubation Duration: 24 hrs (hours)
Experimental Results: Induction of autophagy is stimulated by redistribution of LC3 in U-87MG glioma cells. Autophagy d

Animal/Disease Models: Male C57BL/6 mice (6-8 weeks old) were subjected to RSD (repeated social defeat) and HCC (home cage control) [4]
Doses: 20 mg/kg or 15 mg/kg
Route of Administration: intraperitoneal (ip) injection or administered orally daily for 24 days.
Experimental Results: Reversed RSD-induced social avoidance behavior, Dramatically increased interaction time, and Dramatically diminished stress-induced IL-6 mRNA levels in brain microglia.

Absorption, Distribution and Excretion
Absorption is rapid and good after oral administration (>95%). The primary site of absorption is the small intestine, as the basic amine groups ionize in the acidic environment of the stomach, preventing the drug from penetrating tissues. Bioavailability ranges from 29% to 77% due to significant individual variability. Peak plasma concentrations are typically reached 2–6 hours after oral administration. Food does not affect absorption.
Imipramine is primarily excreted in the urine, with less than 5% remaining unchanged.
Imipramine has a large apparent volume of distribution, 10–20 L/kg. The accumulated concentration in the brain is known to be 30–40 times the systemic circulation concentration.
The mean clearance of imipramine is 1 L/h/kg. The mean clearance of its active metabolite, desipramine, is 1.8 L/h/kg.
Tricyclic antidepressants are well absorbed after oral administration. …After absorption, they are widely distributed. …They bind tightly to plasma proteins and tissue components. /Tricyclic antidepressants
Excretion…rapid…approximately 40% of the radioactive imipramine dose appears in the urine within 24 hours, and 70% is excreted within the first 72 hours. The remainder appears in the feces. A small amount…is recovered as the unaltered drug or an active demethylated derivative. The majority is excreted as N-oxide or unbound or bound 2-OH derivatives.
Placental transport of imipramine and its demethylated derivatives has been observed in animals.
The distribution of intravenously injected (14)C and imipramine in mice was studied using whole-body autoradiography. Five minutes after administration, high uptake of (14)C was observed in the brain, myocardium, lungs, adrenal glands, and kidneys, but low levels of (14)C in the blood. Within 1 hour…(14)C/concentration/…high concentrations were observed in the salivary glands, intestines, liver, gallbladder, and bladder; after 3 hours…primarily confined to organs associated with imipramine excretion…intestines, liver, and kidneys. For more complete data on the absorption, distribution, and excretion of imipramine (8 metabolites), please visit the HSDB record page.

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Metabolism/Metabolites
Imipramine is almost entirely metabolized by the liver. Imipramine is converted to desipramine via CYP1A2, CYP3A4, and CYP2C19. Both imipramine and desipramine are hydroxylated via CYP2D6. Desipramine is an active metabolite. Minor metabolic pathways include dealkylation to form an iminodibenzyl product, and demethylation of desipramine to didesmethylimipramine, followed by hydroxylation. Less than 5% of imipramine is excreted unchanged after oral administration.
...Studies on the metabolism of imipramine and its metabolites in rat liver microsomes...revealed 16 metabolic pathways, including N-demethylation, aromatic ring hydroxylation, side-chain dealkylation, N-oxidation, N-oxide reduction, and conjugation reactions.
Imipramine N-oxide and iminodibenzyl…are identified as other metabolites in human urine.
…In the human body, it is metabolized via N-demethylation and hydroxylation on aromatic rings or vinyl bridges to produce…desmethylimipramine (DMI) and desdimethylimipramine (DDMI), as well as 2-hydroxy and 10-hydroxy derivatives of imipramine, including DMI and DDMI, and their glucuronide conjugates.
Imipramine (half-life 16 hours) can be bioconverted into the active metabolite desmethylimipramine (half-life 18 hours).
Known metabolites of imipramine include imipramine N-glucuronide, desmethylimipramine, and 2-hydroxyimipramine.
Imipramine is primarily metabolized in the liver. In the liver, imipramine is converted into the active metabolites desipramine and 2-hydroxydesipramine by various CYP isoenzymes (e.g., CYP1A2, CYP2D6, CYP3A4, CYP2C9). Elimination pathway: Approximately 40% of the oral dose is excreted in the urine within 24 hours, and 70% within 72 hours. A small amount is excreted in the bile and feces. Half-life: Imipramine - 8-20 hours; Desipramine (active metabolite) - up to 125 hours. The mean half-life of imipramine is 12 hours. The mean half-life of its active metabolite, desipramine, is 22.5 hours. Imipramine (half-life 16 hours)...

Toxicity Summary
Identification: Imipramine is a tricyclic antidepressant. Substance Properties: Imipramine hydrochloride is a white or slightly yellow, odorless or nearly odorless crystalline powder. It is readily soluble in water, ethanol, chloroform, and acetone; practically insoluble in ether. Indications: Treatment of depression; nocturnal enuresis in children. Human Exposure: Major Risks and Target Organs: Affects the parasympathetic nervous system, central nervous system, and cardiovascular system. Clinical Manifestations Overview: Early Symptoms: Dilated pupils, blurred vision, dry mouth, tachycardia, high fever, urinary retention, decreased bowel motility, and central nervous system excitation. Extrapyramidal symptoms may occur. Later, More Serious Manifestations: Seizures, coma, hypotension, arrhythmias, and cardiopulmonary arrest. The progression of the disease can be extremely rapid, from conscious and mild symptoms to life-threatening toxic reactions. Contraindications: Epilepsy, organic brain injury, urinary retention, heart disease, acute glaucoma. Hyperthyroidism and liver disease are relative contraindications. Route of administration: Oral: Preferred route of administration. Injection: Intramuscular injection of imipramine may be used at the beginning of treatment if oral administration is not feasible or appropriate. Absorption route: Oral: Primarily absorbed in the small intestine, with little or no absorption in the stomach. Absorption is almost complete (95%). Peak plasma concentrations occur 2 to 6 hours after administration. Food does not affect absorption, peak concentration, or time to peak concentration. High doses may be absorbed more slowly due to delayed gastric emptying and reduced intestinal motility. Large amounts of imipramine, including intact tablet fragments, have been found in autopsies. Parenteral administration: Absorption appears complete because the recovery rate of urinary metabolites is the same after oral or parenteral administration. Distribution by route of exposure: Imipramine is lipophilic and therefore widely distributed in the body. Its distribution is affected by plasma protein binding. The plasma protein binding rate of imipramine ranges from 60% to 96%. Biological half-life by route of exposure: The half-life of imipramine is approximately 20 hours. The half-life of its active metabolite, desipramine, can reach 125 hours. Metabolism: Imipramine is almost entirely metabolized in the liver, where it is oxidized by microsomal enzymes and then conjugated with glucuronic acid. Imipramine is primarily metabolized to the active metabolite desipramine via demethylation, with a small amount metabolized to 2-hydroxyimipramine via aromatic 2-hydroxylation. Desipramine is metabolized to 2-hydroxydesipramine via aromatic 2-hydroxylation. Quantitatively, hydroxylation is the most important intermediate metabolic pathway for both imipramine and desipramine, and is also the rate-limiting step in their elimination. The plasma elimination half-life of desipramine is longer than that of imipramine, possibly due to its lower hydroxylation rate. Both imipramine and desipramine undergo significant and highly variable first-pass metabolism, the extent of which depends on the oxidative phenotype. In Caucasians, there are slow-metabolizing and fast-metabolizing phenotypes: at least 6.5% to 10% of the population are slow-metabolizing. First-pass metabolism of imipramine and desipramine is reduced in the slow-metabolizing population. Smoking, alcohol consumption, and other medications may affect the metabolism of imipramine and desipramine by altering the mixed-function oxidase system: steady-state plasma concentrations of imipramine are lower in smokers than in non-smokers. Studies have found that the intrinsic clearance of imipramine in alcoholics is three times that of non-smokers. Cimetidine can increase the bioavailability of imipramine by 40% to 75%. Certain drugs, such as haloperidol, disulfiram, and morphine, can prolong toxic effects by inhibiting hydroxylation. Elimination via exposure: After oral administration of imipramine, less than 5% of the dose is excreted unchanged in the urine. The concentration of hydroxy metabolites may be disproportionately elevated in patients with chronic renal failure. Mechanism of action: Toxoplasmosis: Anticholinergic effects: Increased heart rate. Imipramine has a quinidine-like effect on the heart due to slowed sodium influx and potassium efflux, leading to slowed conduction and repolarization. The slowed conduction primarily occurs in the His-Purkinje fiber segment of the atrioventricular conduction system, resulting in prolonged PR and QRS intervals. Prolonged depolarization leads to QT interval prolongation. Peripheral receptor blockade may cause orthostatic hypotension. Pharmacodynamics: The antidepressant mechanism of imipramine is likely through central inhibition of biogenic amine reuptake, primarily affecting norepinephrine and serotonin. In addition to its central effects, imipramine is a competitive antagonist of histamine H1 and H2 receptors. Interactions: Effects on imipramine itself: Imipramine can enhance its effects due to decreased hepatic metabolism, for example, with antipsychotic drugs, methylphenidate, and certain steroids (including oral contraceptives). Imipramine's effects can be decreased due to increased hepatic metabolism, for example, with barbiturates, certain other sedatives, and smoking. Effects of imipramine on other substances: Enhances the effects of alcohol and other central nervous system depressants. Enhances the anticholinergic effects of anticholinergic drugs used to treat Parkinson's disease. Enhances the effects of biogenic amines (such as norepinephrine), which are normally cleared from the site of action via neuronal reuptake. Blocks the effects of indirect-acting amines (such as tyramine). It inhibits the effects of adrenergic neuron blockers (such as guanethidine). It enhances the central nervous system excitatory effects of amphetamine but blocks its peripheral effects. Monoamine oxidase inhibitors can have particularly serious interactions when taken concurrently with tricyclic antidepressants. The resulting syndromes may include severe central nervous system toxicity, manifested as high fever, seizures, and coma. Major adverse reactions: Anticholinergic effects include dry mouth, acidic or metallic taste in the mouth, upper abdominal discomfort, constipation, dizziness, tachycardia, palpitations, blurred vision, and urinary retention. Paradoxically, excessive sweating may also occur. Weakness and fatigue. Elderly patients are more prone to dizziness, orthostatic hypotension, constipation, delayed urination, edema, and muscle tremors. Approximately 10% of treated patients and more than 30% of patients over 50 years of age may experience manic reactions, confusion, or delirium. Extrapyramidal reactions are rare, but tremors are not uncommon. Children may experience withdrawal syndrome, manifested as gastrointestinal symptoms. Imipramine's mechanism of action is to inhibit the reuptake of the neurotransmitters norepinephrine and serotonin by neurons. It binds to sodium-dependent serotonin transporters and sodium-dependent norepinephrine transporters, thereby preventing or reducing the reuptake of norepinephrine and serotonin by nerve cells. Depression is associated with insufficient stimulation of postsynaptic neurons by norepinephrine and serotonin. Slowing the reuptake of these neurotransmitters increases their concentration in the synaptic cleft, which is thought to help alleviate depressive symptoms. In addition to acutely inhibiting neurotransmitter reuptake, long-term use of imipramine also leads to downregulation of cortical β-adrenergic receptors and sensitization of postsynaptic serotonergic receptors. This results in enhanced serotonergic transmission.

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Toxicity Data
LD50: 355 to 682 mg/kg (oral, rat).

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Interactions
A particularly serious but rare interaction has been reported when monoamine oxidase (MAO) inhibitors and tricyclic antidepressants are taken concurrently. Tricyclic antidepressants
...interactions include enhancing the effects of central nervous system depressants, blocking the hypotensive effects of guanethidine, and enhancing the hypertensive effects of sympathomimetic agonists. Interactions with thyroxine, methylphenidate, and phenothiazines, all of which may enhance...the effects...tricyclic antidepressants
Long-term use of imipramine or desipramine significantly increases the cardiotoxicity of digoxin...
They (tricyclic compounds) enhance the effects of antihistamines; anticholinergics and other central nervous system depressants.../tricyclic antidepressants/
For more (complete) data on interactions of imipramine (26 in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in rats: 250 mg/kg
Intraperitoneal LD50 in rats: 79 mg/kg
Subcutaneous LD50 in rats: 250 mg/kg
Intravenous LD50 in rats: 15900 μg/kg
For more complete data on non-human toxicity values of imipramine (8 types), please visit the HSDB record page.

[1]. New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells. Exp Mol Med. 2020 Feb;52(2):281-292.

[2]. The tricyclic antidepressant imipramine induces autophagic cell death in U-87MG glioma cells. Biochem Biophys Res Commun. 2011 Sep 23;413(2):311-7.

[3]. The antidepressants imipramine, clomipramine, and citalopram induce apoptosis in human acute myeloid leukemia HL-60 cells via caspase-3 activation. J Biochem Mol Toxicol. 1999;13(6):338-47.

[4]. Imipramine attenuates neuroinflammatory signaling and reverses stress-induced social avoidance. Brain Behav Immun. 2015 May;46:212-20.

[5]. Evidence for an imipramine-sensitive serotonin transporter in human placental brush-border membranes. J Biol Chem. 1989 Feb 5;264(4):2195-8.

Therapeutic Uses

Adrenergic reuptake inhibitor; Tricyclic antidepressant. Effective for depression, especially bipolar disorder and degenerative psychosis-related depression…/Imipramine hydrochloride/
2-Hydroxyimidamine hydrochloride inhibits the uptake of norepinephrine and serotonin by the synaptosomes in the rat cerebral cortex to the same extent as the parent drug.
This article describes treatments for childhood enuresis, including imipramine.
For more complete data on the therapeutic uses of imipramine (8 types), please visit the HSDB record page.
Drug Warnings

Because use of this drug may cause birth defects…/IT/Contraindicated in early pregnancy. /Imipramine hydrochloride/
Tricyclic antidepressants are contraindicated in patients with congestive heart failure, angina pectoris, and paroxysmal tachycardia; in addition, caution should be exercised in patients with urinary retention, glaucoma, diabetes, impaired liver function, asthma, and a history of epilepsy. Tricyclic antidepressants
A small number of patients may develop physical dependence on tricyclic antidepressants after abruptly discontinuing high doses of imipramine, manifesting as malaise, chills, runny nose, and muscle aches.
While most fatal cases occur after ingestion of more than 1.5 grams, there are reports of death after ingestion of 500 to 750 mg, and reports of recovery after ingestion of 5.4 grams. Imipramine Hydrochloride
For more complete data on drug warnings for imipramine (33 in total), please visit the HSDB record. Page.

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Pharmacodynamics
Imipramine is a tricyclic antidepressant with general pharmacological properties similar to structure-related tricyclic antidepressants such as amitriptyline and doxepin. Imipramine's mechanism of action is to block serotonin and norepinephrine reuptake transporters, but its affinity for the serotonin reuptake transporter is much higher than that for the norepinephrine reuptake transporter. Imipramine's effects are similar to other antidepressants targeting monoamine neurotransmitters, enhancing serotonin and norepinephrine-mediated neurotransmission. This modulation of neurotransmission induces a complex series of changes in brain structure and function, improving depressive symptoms. These changes include increased hippocampal neurogenesis and decreased downregulation of hippocampal neurogenesis during stress responses. These changes suggest that brain-derived neurotrophic factor (BDNF) signaling is essential for antidepressant effects, although its direct link to increased monoamine neurotransmission remains unclear. Drugs targeting serotonin reuptake may also lead to downregulation of β-adrenergic receptors in the brain.

C19H24N2

280.4073

316.17

113-52-0

Imipramine-d4 hydrochloride;61361-33-9;Imipramine;50-49-7;Imipramine-d6;65100-45-0;Imipramine-d3 hydrochloride;112898-42-7

3696

White to off-white solid powder

1.041g/cm3

403.1ºC at 760mmHg

168-1700C

179.7ºC

6.6E-06mmHg at 25°C

4.742

0

2

4

21

291

0

BCGWQEUPMDMJNV-UHFFFAOYSA-N

InChI=1S/C19H24N2/c1-20(2)14-7-15-21-18-10-5-3-8-16(18)12-13-17-9-4-6-11-19(17)21/h3-6,8-11H,7,12-15H2,1-2H3

3-(5,6-dihydrobenzo[b][1]benzazepin-11-yl)-N,N-dimethylpropan-1-amine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~315.59 mM)
H2O : ~62.5 mg/mL (~197.24 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.89 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.89 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (7.89 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 60 mg/mL (189.35 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)