Reboxetine

Reboxetine is a highly selective and potent inhibitor of noradrenaline reuptake. It has only a weak effect on the 5-HT reuptake and does not affect the uptake of dopamine.

Noradrenaline reuptake inhibition and the consequent increase of noradrenaline availability in the synaptic cleft and modification of noradrenergic transmission, reportedly is among the most relevant mechanisms of action of known antidepressant drugs.

In vitro, studies have shown that reboxetine has no significant affinity for adrenergic (α₁, α₂, β) and muscarinic receptors; antagonism of such receptors has been described to be associated with cardiovascular, anticholinergic and sedative side effects of other antidepressant drugs. Reboxetine is devoid of in vitro binding affinity for either α₁ or α₂ adrenoceptors, however, a functional interference with α-adrenoceptors at high doses in vivo cannot be excluded.

After oral administration of a single 4 mg reboxetine dose to healthy volunteers, peak levels of about 130 ng/ml are achieved within 2 h post-dosing. Data indicate that absolute bioavailability is at least 60%.

Reboxetine plasma levels decreased monoexponentially with a half-life of about 13 h. Steady-state conditions are observed within 5 days. Linearity of the pharmacokinetics was shown in the range of single oral doses in the clinically recommended dose-ranges.

The drug appears to be distributed into total body water. Reboxetine is 97 % bound to human plasma proteins in young and 92% in elderly (with affinity markedly higher for α1 acid glycoprotein than albumin), with no significant dependence of the concentration of drug.

Reboxetine is predominantly metabolised in vitro via cytochrome P4503A (CYP3A4). In vitro studies have shown that reboxetine does not inhibit the activity of the following isozymes of cytochrome P450: CYP1A2, CYP2C9, CYP2C19, and CYP2E1. Reboxetine inhibits both CYP2D6 and CYP3A4 with low binding affinities, but has shown no effect on the in vivo clearance of drugs metabolized by these enzymes. Reboxetine should be co-prescribed with caution with potent inhibitors of CYP3A4.

The amount of radioactivity excreted in urine accounts for 78% of the dose. Even though unchanged drug is predominant in the systemic circulation (70% of total radioactivity, in terms of AUC), only 10% of the dose is excreted as unchanged drug in urine. These findings suggest that biotransformation rules the overall elimination of reboxetine and that metabolites excretion is limited by their formation. The main metabolic pathways identified are 2-O-dealkylation, hydroxylation of the ethoxyphenoxy ring and oxidation of the morpholine ring, followed by partial or complete glucuro- or sulpho-conjugation.

The drug is available as a racemic mixture (with both enantiomers being active in the experimental models): no chiral inversion, nor reciprocal pharmacokinetic interferences between enantiomers have been observed. Plasma levels of the more potent SS enantiomer are about two times lower and urinary excretion two times higher than those of the enantiomeric counterpart. No significant differences were observed in the terminal half-lives of the two enantiomers.

Increases in systemic exposure and half-life of approximately two-fold are observed in patients with renal insufficiency and hepatic insufficiency. Similar or somewhat greater (3-fold) increases in systemic exposure also occur in elderly patients relative to young healthy volunteers.

Reboxetine did not induce gene mutations in bacterial or mammalian cells in vitro but induced chromosomal aberrations in human lymphocytes in vitro. Reboxetine did not cause DNA damage in yeast cells or rat hepatocytes in vitro. Reboxetine did not cause chromosomal damage in an in vivo mouse micronucleus test, and did not increase tumor incidence in carcinogenecity studies in mice and rats.

Haemosiderosis was reported in toxicity studies in rats only.

Studies in animals have not demonstrated any teratogenic effect or any effect of the compound on global reproductive performance. In fertility studies in rats, reboxetine did not alter mating behavior, fertility or general reproductive performance at oral doses up to 90 mg/kg/day.

Dosages that produced plasma concentrations within the therapeutic range for humans induced an impairment of growth and development and long term behavioural changes in offspring of rats.

In rats reboxetine is excreted in milk.