Pharmacodynamics<unk>  (and metabolites) Site 77 43 5 3 92 DAT 1,451 5-HT1A >1,000 5-HT1B >1,000 5-HT1D >1,000 5-HT2 2,000 1,000 1,700 5-HT6 >1,000 5-HT7 >1,000 α1 11,400 20,000 19,600 α2A 29,800 >30,000 >10,000 β1 18,000 56,100 32,100 M1 >100,000 >100,000 >100,000 M2 >100,000 >100,000 >100,000 D1 >10,000 >10,000 >10,000 D2 >10,000 >10,000 >10,000 H1 12,100 >100,000 >100,000 422 300 95 σ1 >1,000 GABAA 200 >30,000 >10,000 NMDA 3,470a Kir3.1/3.2 10,900b Kir3.2 12,400b Kir3.1/3.4 6,500b hERG 6,300 20,000 5,710 Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. All values are for human receptors unless otherwise specified. arat cortex. bXenopus oocytes. Additional sources:<unk>  inhibits the presynaptic norepinephrine transporter (NET), preventing the reuptake of norepinephrine throughout the brain along with inhibiting the reuptake of dopamine in specific brain regions such as the prefrontal cortex, where dopamine transporter (DAT) expression is minimal. In rats,<unk>  increased prefrontal cortex catecholamine concentrations without altering dopamine levels in the striatum or nucleus accumbens; in contrast, methylphenidate, a dopamine reuptake inhibitor, was found to increase prefrontal, striatal, and accumbal dopamine levels to the same degree. In addition to rats,<unk>  has also been found to induce similar region-specific catecholamine level alteration in mice.<unk> 's status as a serotonin transporter (SERT) inhibitor at clinical doses in humans is uncertain. A PET imaging study on rhesus monkeys found that<unk>  occupied >90% and >85% of neural NET and SERT, respectively. However, both mouse and rat microdialysis studies have failed to find an increase in extracellular serotonin in the prefrontal cortex following acute or chronic<unk>  treatment. Supporting<unk> 's selectivity, a human study found no effects on platelet serotonin uptake (a marker of SERT inhibition) and inhibition of the pressor effects of tyramine (a marker of NET inhibition).<unk>  has been found to act as an NMDA receptor antagonist in rat cortical neurons at therapeutic concentrations. It causes a use-dependent open-channel block and its binding site overlaps with the Mg2+ binding site.<unk> 's ability to increase prefrontal cortex firing rate in anesthetized rats could not be blocked by D1 or α2-adrenergic receptor antagonists, but could be potentiated by NMDA or an α1-adrenergic receptor antagonist, suggesting a glutaminergic mechanism. In Sprague Dawley rats,<unk>  reduces NR2B protein content without altering transcript levels. Aberrant glutamate and NMDA receptor function have been implicated in the etiology of ADHD.<unk>  also reversibly inhibits GIRK currents in Xenopus oocytes in a concentration-dependent, voltage-independent, and time-independent manner. Kir3.1/3.2 ion channels are opened downstream of M2, α2, D2, and A1 stimulation, as well as other Gi-coupled receptors. Therapeutic concentrations of<unk>  are within range of interacting with GIRKs, especially in CYP2D6 poor metabolizers. It is not known whether this contributes to the therapeutic effects of<unk>  in ADHD. 4-Hydroxyatomoxetine, the major active metabolite of<unk>  in CYP2D6 extensive metabolizers, has been found to have sub-micromolar affinity for opioid receptors, acting as an antagonist at μ-opioid receptors and a partial agonist at κ-opioid receptors. It is not known whether this action at the kappa-opioid receptor leads to CNS-related adverse effects. Pharmacokinetics Orally administered<unk>  is rapidly and completely absorbed. First-pass metabolism by the liver is dependent on CYP2D6 activity, resulting in an absolute bioavailability of 63% for extensive metabolizers and 94% for poor metabolizers. Maximum plasma concentration is reached in 1–2 hours. If taken with food, the maximum plasma concentration decreases by 10-40% and delays the tmax by 3 hours. Drugs affecting gastric pH have no effect on oral bioavailability.<unk>  has a volume of distribution of 0.85 L/kg, with limited partitioning into red blood cells. It is highly bound to plasma proteins (98.7%), mainly albumin, along with α1-acid glycoprotein (77%) and IgG (15%). Its metabolite N-desmethylatomoxetine is 99.1% bound to plasma proteins, while 4-hydroxyatomoxetine is only 66.6% bound. The half-life of<unk>  varies widely between individuals, with an average range of 4.5 to 19 hours. As<unk>  is metabolized by CYP2D6, exposure may be increased 10-fold in CYP2D6 poor metabolizers.<unk> , N-desmethylatomoxetine, and 4-hydroxyatomoxetine produce minimal to no inhibition of CYP1A2 and CYP2C9, but inhibit CYP2D6 in human liver microsomes at concentrations between 3.6-17 μmol/L. Plasma concentrations of 4-hydroxyatomoxetine and N-desmethylatomoxetine at steady state are 1.0% and 5% that of<unk>  in CYP2D6 extensive metabolizers, and are 5% and 45% that of<unk>  in CYP2D6 poor metabolizers.<unk>  is excreted unchanged in urine at 96% and 80% of a total dose being excreted in urine, respectively. The fractions excreted in urine as 4-hydroxyatomoxetine and its glucuronide account for 86% of a given dose in extensive metabolizers, but only 40% in poor metabolizers. CYP2D6 poor metabolizers excrete greater amounts of minor metabolites, namely N-desmethylatomoxetine and 2-hydroxymethylatomoxetine and their conjugates. Major metabolites of<unk>  in humans. Pharmacogenomics Chinese adults homozygous for the hypoactive CYP2D6*10 allele have been found to exhibit two-fold higher area-under-the-curve (AUCs) and 1.5-fold higher maximum plasma concentrations compared to extensive metabolizers. Japanese men homozygous for CYP2D6*10 have similarly been found to experience two-fold higher AUCs compared to extensive metabolizers.
Atomoxetine
Guanfacine
Dapoxetine
Vortioxetine
Edivoxetine
Duloxetine
Fluoxetine
Fluparoxan