Chemical formula: C₂₀H₂₃N Molecular mass: 277.403 g/mol PubChem compound: 4011
Maprotiline hydrochloride is a tetracyclic antidepressant, psychoanaleptics, non-selective mono-amine reuptake inhibitor, which shares a number of basic therapeutic properties with the tricyclic antidepressants. It displays a well-balanced spectrum of action, brightening mood and alleviating anxiety, agitation and psychomotor retardation. In masked depression, it can exert a favourable influence on somatic symptoms.
Maprotiline differs structurally and pharmacologically from the tricyclic antidepressants. It has a potent and selective inhibitory effect on noradrenaline re-uptake in the pre-synaptic neurons of cortical structures in the central nervous system but exerts hardly any inhibitory effect on serotonin re-uptake. Maprotiline shows weak to moderate affinity for central alpha1-adrenoceptors, marked inhibitory activity at histamine H1 receptors and a moderate anticholinergic effect.
Changes in functional responsiveness of the neuroendocrine system (growth hormone, melatonin, endorphinergic system) and/or neurotransmitters (noradrenaline, serotonin, GABA) during long-term treatment are also considered to be involved in the mechanism of action.
Following single oral administration of film-coated tablets, maprotiline hydrochloride is slowly but completely absorbed. The mean absolute bioavailability is approximately 66 to 70%. Within 8 hours of a single oral dose of 50 mg, peak blood concentrations of 48 to 150 nmol/L (13 to 47 ng/mL) are attained.
After repeated oral or intravenous administration of 150 mg maprotiline daily, steady-state blood concentrations of 320 to 1270 nmol/L (100 to 400 ng/mL) are reached during the second week of treatment, whether the amount is given in a single dose or in three fractional doses. Steady-state levels of maprotiline are in linear proportion to the dose, although the concentrations vary greatly from one subject to another.
Peak Plasma concentration is reached after 8-24 hours.
The partition coefficient of maprotiline between blood and plasma is 1.7. The mean apparent distribution volume is 23 to 27 L/kg. Maprotiline is 88 to 90% bound to plasma proteins, independent of the patient’s age or disease. Concentrations in cerebrospinal fluid are 2 to 13% of serum concentrations.
Maprotiline is primarily eliminated through metabolism; only 2 to 4% of the dose is excreted unchanged in the urine. The principal route of metabolism is the formation of the pharmacologically active metabolite, desmethylmaprotiline. Of minor importance are several hydroxylated and/or methoxylated metabolites, which are excreted as conjugates by the kidney. Primary elimination of maprotiline and desmethylmaprotiline is through hydroxylation and further conjugation of the metabolites and excretion in the urine. The hydroxylated metabolites, such as isomeric phenols, 2- and 3-hydroxymaprotiline and 2, 3-dihydrodiol, represent only 4 to 8% of the dose excreted in human urine. The majority of the eliminated products are glucuronide conjugates of the primary metabolites (75%). The demethylation of maprotiline appears to be catalysed primarily by CYP2D6, with some contributions by CYP1A2.
Maprotiline is eliminated from the blood with a mean half-life of approximately 43 to 45 hours. Mean systemic clearance ranges between 510 and 570 mL/min.
Within 21 days, about two thirds of a single dose are excreted in urine, predominantly as free and conjugated metabolites, and about one third in the faeces.
Although concentrations vary significantly from person to person, stable levels of maprotiline are directly proportional to the dose.
The elderly patients may show higher plasma concentrations of maprotiline as a combined result of a decreased metabolism of the drug in elderly patients and a decreased renal function. In elderly patients (aged over 60 years), steady-state concentrations are higher than in younger patients on the same dosage; the apparent elimination half-life is longer, and the daily dose should be halved.
In renal impairment (creatinine clearance 24 to 37 mL/min), the elimination half-life and renal excretion of maprotiline are hardly affected, provided hepatic function is still normal. Renal excretion of metabolites is decreased, but this is compensated by increased elimination via the bile.
In patients with mild to moderate renal impairment and normal hepatic function may usually be treated with normal doses. Maprotiline is contraindicated in patients with severe renal impairment.
Since the drug is primarily eliminated by metabolism, a significant impact on the clearance of the drug is anticipated in patients with hepatic failure. Maprotiline is contraindicated in patients with severe hepatic impairment.
Although the impact of ethnic sensitivity and race on the pharmacokinetics of maprotiline has not been studied extensively, the metabolism of maprotiline is governed by genetic factors leading to poor and extensive metabolism of the drug.
In individuals with CYP2D6 slow metaboliser phenotype (5-10% of the Caucasian population) maprotiline exposure is expected to be ~250% higher than in individuals with fast metaboliser phenotype, giving them a stronger and more prolonged pharmacological effect.
Despite the lack of any reports on the pharmacokinetics of maprotiline and desmethylmaprotiline in individuals with ultrafast metaboliser phenotype, it is thought that the metabolism of maprotiline and desmethylmaprotiline will be accelerated in these individuals. The effect of maprotiline is probably reduced in these individuals and dose adjustment may be necessary.
Preclinical data of maprotiline, based on conventional studies on the toxicity of repeated administration, genotoxicity, mutagenicity, carcinogenic potential for teratogenicity and reproductive toxicity, have shown no special hazard for humans.
Effects in preclinical studies were observed only at doses that were far beyond the maximum doses in humans and therefore have little relevance to clinical use.
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