Absorption, Distribution and Excretion
Following oral administration of a single dose of 210 mg to healthy subjects, lofepramine is rapidly absorbed, with peak plasma concentrations of 140 ng/ml(lofepramine) and 5 ng/ml (desipramine) achieved within 1 and 4 hours, respectively.

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Metabolism / Metabolites
The in vitro metabolism of lofepramine was studied in comparison with imipramine. Both compounds were hydroxylated and demethylated by a NADPH-generating system in rat and human liver microsomes. Three metabolites were in common for the two drugs, namely desipramine (DMI), 2-hydroxydesipramine (2-OH-DMI) and didesmethylimipramine (DDMI). Lofepramine was also metabolized to three unique tricyclic metabolites. Comparisons with authentic reference compounds suggested that two of these metabolites were 2-hydroxylofepramine and desmethyllofepramine. The ratio between the concentrations of DDMI and DMI was higher for lofepramine than imipramine. This is probably due to DDMI formation via two parallel metabolic pathways of lofepramine, i.e. DMI and desmethyllofepramine, respectively. It is speculated that the different metabolic pattern of lofepramine as compared with desipramine and imipramine is of importance for the therapeutic profile of the drug.
Lofepramine is partially metabolized to desipramine by a cytochrome p450 dependent enzyme system on first pass through the liver. It is metabolized by N-dealkylation, hydroxylation, and glucuronidation. The plasma clearance of lofepramine is 686 L/hr. Its main urinary metabolites are desipramine, 2-hydroxydesipramine, and its glucuronide (2-hydroxyimodibenzyl), and the glycine conjugate of p-chlorobenzoic acid.

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Biological Half-Life
The mean elimination half-lives are 1.7 hours for a 70 mg dose and 2.5 hours for a 140 mg dose. Lofepramine has a half-life in the beta phase of about 5 hours (compared with 24 hours for other TCAs).

Interactions
Lofepramine may potentiate alcohol sedation.
Seizures or arrhythmias may be precipitated /SRP: by flumazenil/ in patients with a serious cyclic antidepressant overdose. /Flumazenil/

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Non-Human Toxicity Values
LD50 Mouse oral >2500 mg/kg /Lofepramine hydrochloride/
LD50 Mouse ip 920 mg/kg /Lofepramine hydrochloride/
LD50 Mouse sc >1000 mg/kg /Lofepramine hydrochloride/
LD50 Rat oral >1000 mg/kg /Lofepramine hydrochloride/
For more Non-Human Toxicity Values (Complete) data for LOFEPRAMINE (6 total), please visit the HSDB record page.

[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 dibenzoazepine, a member of monochlorobenzenes, a tertiary amino compound and an aromatic ketone. It has a role as an antidepressant.
A psychotropic IMIPRAMINE derivative that acts as a tricyclic antidepressant and possesses few anticholinergic properties. It is metabolized to DESIPRAMINE.

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Mechanism of Action
Lofepramine is a tricyclic antidepressant that is structurally similar to imipramine and is extensively metabolised to desipramine. In the absence of other major pharmacological effects it appears that its antidepressant activity stems from the facilitation of noradrenergic neurotransmission by uptake inhibition, and possibly by the additional facilitation of serotoninergic neurotransmission.

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Therapeutic Uses
Lofepramine is a tricyclic antidepressant related to imipramine. Meta-analyses were carried out with respect to efficacy and tolerability by combining outcome and adverse reaction from over 20 controlled trials comparing lofepramine with other tricyclic antidepressants. Lofepramine was at least as effective as the comparators with fewer adverse effects. In particular, the risk/benefit ratio seemed superior to the comparators amitriptyline, imipramine, clomipramine, maprotiline and desipramine.
The results of double blind trial in which 139 patients with primary depression were randomly assigned to either lofepramine (46), imipramine (48), or placebo (45) are discussed. After treatment with either active drug, lofepramine or imipramine, the clinical outcome was significantly greater than with placebo. No significant differences were found in clinical responses between lofepramine and imipramine. With regard to reported side effects, however, a statistically significant lower number of severe and/or moderate side effects were reported for the lofepramine group than for the imipramine group.
EXPTL Therapy: In a randomized, placebo-controlled double-blind trial a combination of lofepramine, phenylalanine and vitamin B(12) was found to be effective in relieving the symptoms of multiple sclerosis (MS). The effect occurred within 2-4 weeks, and improved all types of symptoms in all types of MS. The combination was also effective in relieving symptoms in patients with chronic pain and chronic fatigue.
EXPTL Therapy: A double-blind randomised controlled trial of the effect of low dose lofepramine (70 mg once daily) against placebo was carried out on depressed elderly inpatients on general medical wards for the elderly, comparing measures of depression and side-effects between the randomised groups. Patients were identified for the study using the Geriatric Depression Scale (GDS) and the Brief Assessment Schedule Depression Cards (BASDEC). Sixty-three subjects were randomised: 46 patients completed the entire trial of 28 days treatment. BASDEC and GDS were administered on day 8 post-admission, and depressed patients were randomised double-blind to either low dose lofepramine (70 mg daily) (n = 23) or placebo (n = 23). Assessment of changes in depressive states were made using the Montgomery Asberg Depression Rating Scale (MADRS) on days 8, 18 and 36 post-admission. Both groups improved by a similar amount during the trial. Lofepramine tended to be more effective than placebo in those patients who were more depressed (GDS > or = 18). On the other hand, subjects who were less depressed (i.e. GDS < 18) improved more on placebo than lofepramine. Low dose lofepramine may prove useful in moderately or severely depressed patients treated for only 4 weeks. However, low dose lofepramine is not indicated for mild (GDS 15-18) depression.

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Drug Warnings
Dry mouth is the most common side effect. Constipation, dizziness, sweating, nausea/vomiting, tremor palpitation, blurred vision, drowsiness, fatigue, headache, and insomnia were also observed during clinical studies. There does not appear to be a correlation between plasma lofepramine levels and adverse effects.
Lofepramine is a tricyclic antidepressant that is structurally similar to imipramine ... . Dry mouth is the most commonly reported side effect of usual therapeutic doses of lofepramine, but the incidence of this and other anticholinergic side effects is less among patients treated with lofepramine than with imipramine. Lofepramine has not been associated with adverse effects on cardiac function even in cases of attempted suicide by overdose.
Physostigmine should not be used as an antidote for cyclic antidepressant overdose because it may worsen cardiac conduction disturbances, cause bradyarrhythmias or asystole, and aggravate or precipitate seizures. /Physostigmine/

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.)