Rats administered desipramine hydrochloride for a duration of 14 days exhibited a dose-dependent decrease in the expression of norepinephrine transporter (NET). This was demonstrated by a decrease in the specific binding of 3H-nisoxetine to NET in cerebral cortex preparations (F(3,16) =4.33, p<0.05), as well as in the hippocampus (F(3,16) =4.34, p<0.05). When plasma and brain concentrations of desipramine hydrochloride and desmethyldesipramine hydrochloride were undetectable (that is, below the assay's 25 ng detection limit), this NET downregulation was discovered two days after long-term desipramine hydrochloride treatment was stopped[2].

Absorption, Distribution and Excretion
Desipramine hydrochloride is rapidly and almost completely absorbed from the gastrointestinal tract. It undergoes extensive first-pass metabolism. Peak plasma concentrations are attained 4 - 6 hours following oral administration.
Desipramine is metabolized in the liver, and approximately 70% is excreted in the urine.
...DESIPRAMINE /WAS GIVEN/ IN DOSE OF 25 MG EVERY 8 HR TO 15 PT. .../IT/ ACCUM IN BODY FOR PERIODS VARYING FROM 1 TO 16 DAYS, PEAK PLASMA LEVELS RANGING FROM 10 TO 275 UG/L...
IN ANIMALS, TRANSPLACENTAL PASSAGE HAS BEEN DEMONSTRATED RECENTLY OF...DESIPRAMINE...
AFTER IV ADMIN OF SINGLE DOSE OF DESMETHYLIMIPRAMINE...TO DOGS, RATE OF RENAL EXCRETION OF UNCHANGED DRUG DECR DRAMATICALLY IN INCREASING URINARY PH, WITH LITTLE CHANGE IN CREATININE CLEARANCE. ... URINARY EXCRETION...IN MAN WAS ALSO SHOWN TO BE PH-DEPENDENT...
THERE IS WIDE INTERPATIENT VARIATION IN STEADY-STATE PLASMA CONCN OF TRICYCLIC ANTIDEPRESSANTS. ...VARIATION SEEMS TO BE GENETICALLY DETERMINED... /TRICYCLIC ANTIDEPRESSANTS/
For more Absorption, Distribution and Excretion (Complete) data for DESIPRAMINE (6 total), please visit the HSDB record page.

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Metabolism / Metabolites
Desipramine is extensively metabolized in the liver by CYP2D6 (major) and CYP1A2 (minor) to 2-hydroxydesipramine, an active metabolite. 2-hydroxydesipramine is thought to retain some amine reuptake inhibition and may possess cardiac depressant activity. The 2-hydroxylation metabolic pathway of desipramine is under genetic control.
DEMETHYLIMIPRAMINE YIELDS BISDEMETHYLIMIPRAMINE, DEMETHYL-2-HYDROXYIMIPRAMINE, DEMETHYL-10-HYDROXYIMIPRAMINE, & IMINODIBENZYL IN MAN. /FROM TABLE/
DEMETHYLIMIPRAMINE YIELDS IMIPRAMINE IN RABBITS AND IN RATS. /FROM TABLE/
Desipramine has known human metabolites that include 2-hydroxy-desipramine and Desipramine N-glucuronide.
Desipramine is a known human metabolite of imipramine.
Desipramine is extensively metabolized in the liver by CYP2D6 (major) and CYP1A2 (minor) to 2-hydroxydesipramine, an active metabolite. 2-hydroxydesipramine is thought to retain some amine reuptake inhibition and may possess cardiac depressant activity. The 2-hydroxylation metabolic pathway of desipramine is under genetic control.
Route of Elimination: Desipramine is metabolized in the liver, and approximately 70% is excreted in the urine.
Half Life: 7-60+ hours; 70% eliminated renally

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Biological Half-Life
7-60+ hours; 70% eliminated renally
...DESIPRAMINE /WAS GIVEN/ IN DOSE OF 25 MG EVERY 8 HR TO 15 PT. ...BIOLOGICAL HALF-LIFE...FROM A FEW HR TO MORE THAN 2 DAYS...

Toxicity Summary
Desipramine is a tricyclic antidepressant (TCA) that selectively blocks reuptake of norepinephrine (noradrenaline) from the neuronal synapse. It also inhibits serotonin reuptake, but to a lesser extent compared to tertiary amine TCAs such as imipramine. Inhibition of neurotransmitter reuptake increases stimulation of the post-synaptic neuron. Chronic use of desipramine also leads to down-regulation of beta-adrenergic receptors in the cerebral cortex and sensitization of serotonergic receptors. An overall increase in serotonergic transmission likely confers desipramine its antidepressant effects. Desipramine also possesses minor anticholinergic activity, through its affinity for muscarinic receptors. TCAs are believed to act by restoring normal levels of neurotransmitters via synaptic reuptake inhibition and by increasing serotonergic neurotransmission via serotonergic receptor sensitization in the central nervous system.

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Toxicity Data
LD50: 290 mg/kg (Mouse) (A308)
LD50: 320 mg/kg (Rat) (A308)

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Interactions
ADMIN OF TRICYCLIC ANTIDEPRESSANTS...WITH OR SHORTLY AFTER...MAO INHIBITORS HAS RESULTED IN SEVERE REACTIONS. ... OTHER INTERACTIONS INCL POTENTIATION OF CENTRAL DEPRESSANT DRUGS, BLOCKADE OF ANTIHYPERTENSIVE EFFECTS OF GUANETHIDINE, & AUGMENTATION OF PRESSOR EFFECTS OF SYMPATHOMIMETIC AMINES. /TRICYCLIC ANTIDEPRESSANTS/
Concurrent use /of thyroid hormones/ with tricyclic antidepressants may increase the therapeutic and toxic effects of both medications, possibly due to increased receptor sensitivity to catecholamines; toxic effects include cardiac arrhythmias and CNS stimulation. /Tricyclic antidepressants/
Concurrent use /of sympathomimetics/ with tricyclic antidepressants may potentiate cardiovascular effects possibly resulting in arrhythmias, tachycardia, or severe hypertension or hyperpyrexia; phentolamine can control the adverse reaction. Significant systemic absorption of ophthalmic epinephrine may also potentiate cardiovascular effects; also, local anesthetics with vasoconstrictors should be avoided or a minimal amount of the vasoconstrictor should be used with the local anesthetic. Concurrent use with tricyclic antidepressants may decrease the pressor effect of ephedrine and mephentermine. /Tricyclic antidepressants/
If significant systemic absorption occurs, concurrent use /of ophthalmic naphazoline, nasal or ophthalmic oxymetazoline, nasal or ophthalmic phenylephrine, or nasal xylometazoline/ with tricyclic antidepressants may potentiate pressor effects of these medications. /Tricyclic antidepressants/
For more Interactions (Complete) data for DESIPRAMINE (20 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 375 mg/kg
LD50 Rat ip 48 mg/kg
LD50 Rat sc 183 mg/kg
LD50 Rat iv 29 mg/kg
For more Non-Human Toxicity Values (Complete) data for DESIPRAMINE (8 total), please visit the HSDB record page.

[1]. Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci. 2003 Jan;4(1):13-25.

[2]. Norepinephrine transporter regulation mediates the long-term behavioral effects of the antidepressant desipramine. Neuropsychopharmacology. 2008 Dec;33(13):3190-200.

Therapeutic Uses
Adrenergic Uptake Inhibitors; Antidepressive Agents, Tricyclic
...USED IN MANAGEMENT OF DEPRESSIVE STATES. DESIPRAMINE IS REPORTED TO BE OF BENEFIT IN ENDOGENOUS DEPRESSIONS SUCH AS MANIC DEPRESSIVE REACTIONS, & REACTIVE DEPRESSIONS.
...IF...GIVEN OVER PERIOD OF TIME TO DEPRESSED PATIENTS, ELEVATION OF MOOD OCCURS. ... 2-3 WK...BEFORE THERAPEUTIC EFFECTS...EVIDENT. /IMIPRAMINE/
ANTIDEPRESSANT
For more Therapeutic Uses (Complete) data for DESIPRAMINE (13 total), please visit the HSDB record page.

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Drug Warnings
SINCE TRICYCLIC ANTIDEPRESSANTS CAN CAUSE ORTHOSTATIC HYPOTENSION, PRODUCE ARRHYTHMIAS, & INTERACT IN DELETERIOUS WAYS WITH OTHER DRUGS...GREAT CAUTION MUST BE OBSERVED IN THEIR USE IN PT WITH SIGNIFICANT CARDIAC DISEASE. /TRICYCLIC ANTIDEPRESSANTS/
SPECIAL PRECAUTIONS SHOULD BE TAKEN IN PT WITH BENIGN PROSTATIC HYPERTROPHY. /IMIPRAMINE/
DESIPRAMINE HYDROCHLORIDE IS CONTRAINDICATED IN PATIENTS ON MONOAMINE OXIDASE-INHIBITOR THERAPY. .../IT/ SHOULD NOT BE GIVEN TO PT WITH GLAUCOMA, URETHRAL OR URETERAL SPASM, OR THOSE WHO HAVE HAD MYOCARDIAL INFARCTION WITHIN 3 WK. IT IS ALSO CONTRAINDICATED IN PT WITH SEVERE CORONARY HEART DISEASES OR WITH ACTIVE EPILEPSY. /HYDROGEN CHLORIDE/
The most common adverse effects of tricyclic antidepressants are those which result from anticholinergic activity. These include dry mucous membranes (occasionally associated with sublingual adenitis), blurred vision resulting from mydriasis and cycloplegia, increased intraocular pressure, hyperthermia, constipation, adynamic ileus, urinary retention, delayed micturition, and dilation of the urinary tract. The drugs have been reported to reduce the tone of the esophagogastric sphincter and to induce hiatal hernia in susceptible individuals or to exacerbate the condition in patients with preexisting hiatal hernias. Tricyclic antidepressants should be withdrawn if symptoms of esophageal reflux develop; if antidepressant therapy is essential, a cautious trial of a cholinergic agent such as bethanechol used concomitantly with the antidepressant may be warranted. Anticholinergic effects appear to occur most frequently in geriatric patients, but constipation is frequent in children receiving tricyclic antidepressants for functional enuresis. /Tricyclic antidepressants/
For more Drug Warnings (Complete) data for DESIPRAMINE (24 total), please visit the HSDB record page.

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Pharmacodynamics
Desipramine, a secondary amine tricyclic antidepressant, is structurally related to both the skeletal muscle relaxant cyclobenzaprine and the thioxanthene antipsychotics such as thiothixene. It is the active metabolite of imipramine, a tertiary amine TCA. The acute effects of desipramine include inhibition of noradrenaline re-uptake at noradrenergic nerve endings and inhibition of serotonin (5-hydroxy tryptamine, 5HT) re-uptake at the serotoninergic nerve endings in the central nervous system. Desipramine exhibits greater noradrenergic re-uptake inhibition compared to the tertiary amine TCA imipramine. In addition to inhibiting neurotransmitter re-uptake, desipramine down-regulates beta-adrenergic receptors in the cerebral cortex and sensitizes serotonergic receptors with chronic use. The overall effect is increased serotonergic transmission. Antidepressant effects are typically observed 2 - 4 weeks following the onset of therapy though some patients may require up to 8 weeks of therapy prior to symptom improvement. Patients experiencing more severe depressive episodes may respond quicker than those with mild depressive symptoms.

C18H22N2.HCL

302.84162

302.154

58-28-6

Desipramine-d3;65100-49-4;Desipramine;50-47-5;Desipramine-d4;61361-34-0

2995

White to off-white solid powder

407.4ºC at 760 mmHg

214-216ºC

160.5ºC

4.79

1

2

4

20

267

0

HCYAFALTSJYZDH-UHFFFAOYSA-N

InChI=1S/C18H22N2/c1-19-13-6-14-20-17-9-4-2-7-15(17)11-12-16-8-3-5-10-18(16)20/h2-5,7-10,19H,6,11-14H2,1H3

3-(5,6-dihydrobenzo[b][1]benzazepin-11-yl)-N-methylpropan-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 (~330.21 mM)
H2O : ~100 mg/mL (~330.21 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.26 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 (8.26 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 (8.26 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: 1 mg/mL (3.30 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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