Lofepramine targets the serotonin transporter (SERT) and norepinephrine transporter (NET), inhibiting reuptake of both neurotransmitters. It also produces inhibition of liver tryptophan pyrrolase activity in vitro. The antidepressant activity results from promoting noradrenergic and serotonergic neurotransmission by uptake inhibition. It has weak anticholinergic properties.

Lofepramine produces inhibition of liver tryptophan pyrrolase activity in vitro. This effect is related to its modulation of tryptophan metabolism. As an SNRI, it inhibits neuronal uptake of serotonin and norepinephrine in cellular assays. These activities contribute to its antidepressant properties observed in vivo.

Lofepramine displays antidepressant properties in vivo. It has been studied in the forced swim test and olfactory bulbectomized rat models of depression. It demonstrates significant anxiolytic efficacy in addition to its antidepressant properties. Clinically, it shows robust antidepressant efficacy with notable anxiolytic properties.

Non-cell-based transporter binding assays for Lofepramine use membrane preparations from cells expressing human serotonin or norepinephrine transporters. The compound is incubated with radiolabeled substrate (e.g., [3H]5-HT or [3H]NE) at varying concentrations. Inhibition of substrate uptake or binding affinity (Ki) is determined. Tryptophan pyrrolase activity assays use liver homogenates to measure enzyme inhibition.

Cellular assays for Lofepramine utilize cell lines expressing SERT or NET to measure inhibition of neurotransmitter uptake. Cells are incubated with the compound at various concentrations, followed by addition of radiolabeled 5-HT or NE. Uptake is measured by scintillation counting. IC50 values for reuptake inhibition are determined. Tryptophan metabolism assays may be performed in hepatocyte cultures.

In vivo animal models for Lofepramine include the forced swim test and olfactory bulbectomized rat models of depression. The compound is administered orally or intraperitoneally at various doses. Antidepressant efficacy is assessed by measuring immobility time in the forced swim test or behavioral changes in bulbectomized rats. Anxiolytic effects are evaluated in additional behavioral paradigms.

Absorption, Distribution and Excretion
Following a single oral dose of 210 mg lofepramine in healthy subjects, lofepramine was rapidly absorbed, with peak plasma concentrations of 140 ng/ml (lofepramine) and 5 ng/ml (desipramine), reached within 1 hour and 4 hours, respectively. Metabolism/Metabolites This study compared the in vitro metabolism of lofepramine and imipramine. Both compounds can be hydroxylated and demethylated in rat and human liver microsomes via the NADPH generation system. Both drugs share three metabolites: desipramine (DMI), 2-hydroxydesipramine (2-OH-DMI), and bis(desipramine) (DDMI). Lofepramine can also be metabolized into three distinct tricyclic metabolites. Comparison with the standard reference compound showed that two of these metabolites are 2-hydroxylofepramine and desipramine. The DDMI/DMI concentration ratio of lofepramine was higher than that of imipramine. This may be due to the existence of two parallel metabolic pathways for lofepramine, namely DMI and desmethyllofepramine, which generate DDMI. It is speculated that the different metabolic pathways of lofepramine compared to desipramine and imipramine are significant for the therapeutic properties of this drug. During first-pass metabolism in the liver, lofepramine is partially metabolized to desipramine via a cytochrome P450-dependent enzyme system. Its metabolic pathway includes N-dealkylation, hydroxylation, and glucuronidation. The plasma clearance of lofepramine is 686 L/hr. Its major urinary metabolites are desipramine, 2-hydroxydesipramine and its glucuronide (2-hydroxyimodimbinyl), and a glycine conjugate of p-chlorobenzoic acid.

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Biological Half-Life
The mean elimination half-life is 1.7 hours in the 70 mg dose group and 2.5 hours in the 140 mg dose group. Lofepramine has a β-phase half-life of approximately 5 hours (compared to 24 hours for other tricyclic antidepressants).
Pharmacokinetic properties of Lofepramine include molecular weight of 418.97 g/mol and molecular formula C26H27ClN2O. It is extensively metabolized to desipramine. The N-substituted acetophenone moiety alters its pharmacokinetic and toxicological profile while retaining antidepressant efficacy. Storage: +4°C.

Interactions
Lofepramine may enhance the sedative effect of alcohol. In patients with severe overdose of cyclic antidepressants, flumazenil may induce seizures or arrhythmias. Non-Human Toxicity Values Mice oral LD50 >2500 mg/kg /lofepramine hydrochloride/ Mice intraperitoneal LD50 920 mg/kg /lofepramine hydrochloride/ Mice subcutaneous LD50 >1000 mg/kg /lofepramine hydrochloride/ Rat oral LD50 >1000 mg/kg /lofepramine hydrochloride/ For more non-human toxicity values (complete data) for lofepramine (6 out of 6), please visit the HSDB record page.
Lofepramine has weak anticholinergic properties, which may confer a more favorable side effect profile compared to other TCAs. It is a psychoactive drug belonging to the tricyclic antidepressant class. Detailed toxicity data are not extensively reported, but TCAs generally have cardiovascular and central nervous system side effects.

[1]. Lofepramine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. Drugs. 1989 Feb;37(2):123-40.

Lofepramine is a dibenzodiazepine, belonging to the monochlorobenzene, tertiary amine, and aromatic ketone classes. It is an antidepressant. Lofepramine is a psychoactive drug, a derivative of imipramine, belonging to the tricyclic antidepressant class with weak anticholinergic properties. It is metabolized to desipramine. Mechanism of Action: Lofepramine is a tricyclic antidepressant with a structure similar to imipramine and is extensively metabolized to desipramine. In the absence of other major pharmacological effects, its antidepressant activity appears to derive from promoting noradrenergic neurotransmission by inhibiting norepinephrine uptake, and possibly by promoting serotonergic neurotransmission. Therapeutic Uses: Lofepramine is a tricyclic antidepressant associated with imipramine. This study conducted a meta-analysis comparing the efficacy and tolerability of lofepramine with other tricyclic antidepressants by integrating results and adverse reaction data from more than 20 controlled trials. Results showed that lofepramine was at least as effective as the control drug with fewer adverse reactions. Notably, its risk-benefit ratio appeared to be superior to amitriptyline, imipramine, clomipramine, maprotiline, and desipramine. This article discusses the results of a double-blind trial that randomized 139 patients with primary depression to a lofepramine group (n=46), an imipramine group (n=48), or a placebo group (n=45). After treatment, both the lofepramine and imipramine groups showed significantly better clinical efficacy than the placebo group. There was no significant difference in clinical response between the lofepramine and imipramine groups. However, regarding reported side effects, the number of serious and/or moderate side effects reported in the lofepramine group was significantly lower than that in the imipramine group. EXPTL therapy: In a randomized, placebo-controlled, double-blind trial, the combination of lofepramine, phenylalanine, and vitamin B12 was shown to effectively alleviate symptoms of multiple sclerosis (MS). The efficacy was observed within 2–4 weeks and improved all symptoms of all types of MS. This combination also effectively relieved symptoms in patients with chronic pain and chronic fatigue.
EXPTL therapy: A double-blind, randomized, controlled trial in hospitalized elderly patients with depression compared the efficacy of low-dose rofepramine (70 mg once daily) with placebo. The trial included elderly hospitalized patients with depression in a geriatric general medicine ward and compared depressive symptoms and side effects in randomized groups. Patients were screened using the Geriatric Depression Scale (GDS) and the Brief Depression Assessment Card (BASDEC). A total of 63 subjects were enrolled, of whom 46 completed the 28-day treatment. BASDEC and GDS assessments were performed on day 8 of admission, followed by double-blind randomization to receive either low-dose rofepramine (70 mg daily) (n = 23) or placebo (n = 23). Changes in depressive status were assessed using the Montgomery-Osberg Depression Rating Scale (MADRS) on days 8, 18, and 36 of admission. During the trial, both groups of patients showed similar levels of improvement in depression. For patients with higher levels of depression (GDS ≥ 18), lofepramine was generally more effective than placebo. Conversely, for patients with lower levels of depression (GDS < 18), the placebo group showed greater improvement than the lofepramine group. Low-dose lofepramine may be effective for patients with moderate to severe depression, but the treatment duration is only 4 weeks. However, low-dose lofepramine is not suitable for mild depression (GDS score 15–18). Drug Warnings Dry mouth is the most common side effect. Constipation, dizziness, sweating, nausea/vomiting, tremor, palpitations, blurred vision, drowsiness, fatigue, headache, and insomnia have also been observed in clinical studies. There appears to be no correlation between plasma lofepramine levels and adverse reactions. Lofepramine is a tricyclic antidepressant with a structure similar to imipramine… Dry mouth is the most common side effect of commonly used therapeutic doses of lofepramine, but compared to imipramine, patients treated with lofepramine experience a lower incidence of dry mouth and other anticholinergic side effects. Even in cases of attempted suicide due to lofepramine overdose, no adverse effects on cardiac function have been observed. Physostigmine should not be used as an antidote for overdose of cyclic antidepressants, as it may worsen cardiac conduction disorders, causing bradycardia or cardiac arrest, and may exacerbate or induce seizures. /Pysostigmine/
Lofepramine is also known as Lopramine and Leo 640. It has CAS number 23047-25-8. The compound is used clinically as an antidepressant and is a valuable research tool for studying monoaminergic signaling, mood regulation, and the pharmacology of tricyclic antidepressants. It is metabolized to desipramine.

C26H27CLN2O

418.97

418.181

23047-25-8

Lofepramine hydrochloride;26786-32-3;Lofepramine-d3;1185083-78-6

3947

White to yellow solid powder

1.173g/cm3

575ºC at 760mmHg

104-406 °C

301.6ºC

3.17E-13mmHg at 25°C

1.607

5.846

0

3

7

30

523

0

SAPNXPWPAUFAJU-UHFFFAOYSA-N

InChI=1S/C26H27ClN2O/c1-28(19-26(30)22-13-15-23(27)16-14-22)17-6-18-29-24-9-4-2-7-20(24)11-12-21-8-3-5-10-25(21)29/h2-5,7-10,13-16H,6,11-12,17-19H2,1H3

1-(4-chlorophenyl)-2-[3-(5,6-dihydrobenzo[b][1]benzazepin-11-yl)propyl-methylamino]ethanone

Amplit; HSDB 7184; Lofepramine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO : ~50 mg/mL (~119.34 mM)

Solubility in Formulation 1: 2.08 mg/mL (4.96 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 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 2: ≥ 2.08 mg/mL (4.96 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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