Placebo and nisoxetine (10-20 mg b.d. for 7 days) were administered to normal volunteers in a single-bind crossover study. Adverse side effects were minimal. There were no significant changes in heart rate or blood pressure seen when no other drugs were given. The effect of nisoxetine on uptake of biogenic amines was utilized to study its mechanism of action.

It was investigated the interaction of nisoxetine with the human norepinephrine transporter by examining the binding of this ligand to the placental brush border membranes. Scatchard analysis revealed that nisoxetine bound with high affinity to a single class of binding sites in the membranes (dissociation constant = 13.8 +/- 0.4 nM). This value obtained from equilibrium experiments matched the value (11.2 nM) which was calculated using the association and dissociation rate constants. The maximal binding capacity (Bmax) was 5.1 +/- 0.1 pmol/mg of protein. The binding exhibited an absolute requirement for Na+ as well as Cl-. Presence of these ions enhanced the binding affinity without affecting Bmax. Kinetic analyses revealed that the coupling ratio of Na+/nisoxetine was 2, whereas the coupling ratio of Cl-/nisoxetine was 1.