Atomoxetine
Pharmacodynamics
Atomoxetine blocks presynaptic noradrenaline transporter (NET) much more selective then for other monoamine transporters; with a 5nM Ki value in the experiment with radiobinding transporters indicating the high affinity (77nM and 1451nM for 5-HT and dopamine transporters respectively) (Bymaster et al., 2002). Inhibiting this transporter blocks reuptake of noradrenaline and increases circulating concentration of this neurotransmitter. Atomoxetine also induce dopamine release at prefrontal cortex (Bymaster et al., 2002), as this region is lack of dopamine transports and so the dopamine concentration is regulated by NET. The increase in noradrenaline (an adrenoceptor agonist) release may cause sympathetic effects such as vasoconstriction and acceleration of heart rate and result in tachycardia and dysrhythmias.

Pharmacokinetics
Atomoxetine is dosed according to weights of patients (Saucer et al., 2005). It is orally administered with fine absorption, bioavailability = 0.63 and 0.94 for extensive metaboliser (EM) and poor metaboliser (PM) respectively (Saucer et al., 2005), with maximum plasma concentration achieved after 2 to 3 hours (Allen et al., 2004). Once-daily dosing in the morning can be as effective as twice-daily dosing in EM with its effect last to evening and the next morning (Allen et al., 2004), and it is convenient for the patients. Atomoxetine has high plasm protein binding affinity, 98.7% and 96.5% EM and PM respectively (Chalon et al., 2003), so administration with high protein foods may decrease absorption rate. It is then metabolised by Cytochrome P450 in liver.

Oxidising atomoxetine to its major metabolite 4-hydroxyatomoxetine by Cyp2D6 is phase I metabolism, with some N-desmethylatomoxetine also observed (Long et al., 2003). Therefore, its metabolism pathway encounters polymorphism with the bimodal population