Pharmacology and pharmacokinetics of milnacipran.

Milnacipran is a dual-action antidepressant drug with equivalent inhibitory action at noradrenaline and serotonin neuronal reuptake systems. This dual action has been demonstrated in vitro and in vivo in experimental animals, and ex vivo in man. Milnacipran has no relevant affinity for any neurotransmitter receptor studied, in particular postsynaptic adrenergic, muscarinic and histamine receptors, and is therefore expected to be devoid of the prominent side-effects of many earlier antidepressants. Studies in human volunteers have not demonstrated any impact of milnacipran on cognitive function, consistent with its lack of anticholinergic properties. These pharmacodynamic properties are well preserved in vivo in humans, because milnacipran is only metabolized to a limited extent, and therefore circulates in the body principally as the unchanged parent drug, which is the only pharmacologically active compound at clinical doses. The pharmacokinetic profile of milnacipran is characterized by rapid absorption, high bioavailability, low protein binding, and rapid elimination, both by hepatic glucuronidation and renal excretion. This gives milnacipran certain pharmacokinetic advantages, such as low inter-individual variation in plasma levels, low potential for drug interactions, and limited impact on hepatic cytochrome P450 systems. These pharmacokinetic properties differentiate milnacipran from most other antidepressant drugs and contribute to the good safety profile of milnacipran and allow it to be used simply and flexibly in clinical practice.