General
Preferred name
atomoxetine
Synonyms
ATOMOXETINE HYDROCHLORIDE ()
Tomoxetine ()
Tomoxetine hydrochloride ()
(R)-Tomoxetine hydrochloride ()
LY 139603 ()
Atomoxetine HCl ()
LY 139603 HCl ()
Atomoxetine (hydrochloride) ()
Tomoxetine (hydrochloride) ()
(R)-Tomoxetine (hydrochloride) ()
NSC-759104 ()
Strattera ()
LY-139603 ()
Atomoxetine (as hydrochloride) ()
P&D ID
PD010121
CAS
83015-26-3
1027094-45-6
82248-59-7
Tags
natural product
drug
available
Approved by
FDA
First approval
2002
Drug Status
approved
Drug indication
Attention deficit hyperactivity disorder
Max Phase
Phase 4
Structure
Probe scores
P&D probe-likeness score
[[ v.score ]]%
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
HALF-LIFE The reported half-life will be depending on the CYP2D6 metabolization state of the individual and it can range from 3 to 5.6 hours.[A175669]
ROE Studies using radiolabelled atomoxetine showed an over than 80% recovery in urine as metabolites and less than 3% as the unchanged drug. This study indicates that the main elimination route is through extensive hepatic metabolism and a minimal direct renal clearance.[A175669]
PHARMACODYNAMICS The increase in the level of norepinephrine in the central nervous system has been shown to improve the higher cognitive functions of ADHD patients. On the other hand, atomoxetine has been shown to increase the extracellular levels of dopamine specifically in the prefrontal cortex by modulating the cortical synaptic dopamine uptake via the norepinephrine transporter.[A175669] The specific effect in the prefrontal cortex is explained by the fact that in this region dopamine is taken up by norepinephrine transporters. However, atomoxetine presents a very low affinity of other serotonin and dopamine sites which prevents the augmentation of dopamine in nucleus accumbens and reward pathways in the striatum for which this drug presents a very limited abuse potential.[A175750] In preclinical trials, atomoxetine was shown to increase norepinephrine in different regions such as occipital cortex, lateral hypothalamus, dorsal hippocampus and cerebellum. The specificity in the increase of norepinephrine is important as its presence in prefrontal cortex is linked to enhanced attention and higher cognitive processes.[A175750] Clinial trials have shown positive efficiency results of using atomoxetine and improve symptoms of oppositional defiant disorder. However, clinical trials have failed in showing efficiency for depression, bipolar state, Tourette syndrome, dyslexia, and anxiety disorders even when presented as a comorbid condition with ADHD.[A175723] In summary, some of the pharmacodynamic features of atomoxetine to consider are a reduction of anxiety, longer duration of action that provides a smooth effect and reduces the critical time points found in other similar medications and the rebound effects, lack of sleep disturbance, tics and abuse potential. However, atomoxetine effect is longer to be reached, its effect is more discrete when compared to other drugs, and the presence of side effects have a longer to wash out.[A175750] It is important to consider that as atomoxetine acts directly in norepinephrine, it may have some cardiovascular effects caused by the increase of noradrenaline in peripheral neurons.[T244]
MOA Atomoxetine is known to be a nonstimulant potent and selective inhibitor of the norepinephrine transporter which in order will increase the level of free intrasynaptic atomoxetine.[A175723] It has been registered that in the frontal cortex, dopamine is sensitive to norepinephrine receptors and hence, atomoxetine action produces an increase in dopamine in this brain region.[T351, T493] Beneath this commonly known mechanism of action on norepinephrine transporters, it has been seen in pre-clinical studies in rhesus monkeys that atomoxetine also occupates the serotonin transporters which opens the mechanism of action of atomoxetine to what was previously confirmed.[A175669]
INDICATION Atomoxetine is recommended for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adults. It is recommended as a monotherapy in youths that do not respond correctly to stimulants.[A175723] ADHD is a neurodevelopmental disorder that can be categorized as a mental health condition. The symptoms of this condition start at childhood but they continue in adolescence and adulthood. The risk factors of ADHD are variable and they include the consumption of cigarettes, alcohol or drugs during pregnancy, low brain weight, brain injuries, toxical exposure or genetic disorders. The main symptoms for this condition are difficult in paying attention, overactivity and impulsivity.[L5665]
TOXICITY The LD50 of oral administration of atomoxetine in the rat is higher than 300 mg/kg.[MSDS] During clinical trials, there weren't reports of clinical overdose, however, there have been reported fatalities in postmarketing surveillance in patients consuming atomoxetine plus at least another additional drug. There are no reports of fatalities of atomoxetine monotherapy even at high doses of 1400 mg. Some symptoms of overdose are seizures, gastrointestinal symptoms, somnolence, dizziness, tremor, abnormal behavior, hyperactivity, agitation, increased blood pressure, tachycardia, dry mouth, mydriasis, QT prolongation, disorientation, and hallucinations. In case of overdose, dialysis does not work due to high protein binding.[FDA label] Atomoxetine was not found to be carcinogenic, not mutagenic not to impair fertility even in high doses. However, atomoxetine was shown to increase in the incidence diplochromosomes suggesting endoreduplication potential.[FDA label]
METABOLISM Atomoxetine metabolism has been extensively studied and it is known to be characterized by a phase I observed as reactions of aromatic ring hydroxylation, benzylic oxidation and N-demethylation and by a phase II whose profile is defined by O-glucuronidation. One of the major active phase I metabolites of atomoxetine produced by the activity of CYP2D6 is 4-hydroxyatomoxetine which can also be found in saliva. This metabolite is further glucuronidated to form the main urine metabolite 4-hydroxyatomoxetine-O-glucuronide.[A175669] Some of the minor metabolites formed by the action of CYP2C19 is N-desmethylatomoxetine which is further hydroxylated by CYP2D6 followed by glucuronidation. It is important to mention that N-demethylatomoxetine and 4-hydroxyatomoxetine significantly bind to the same plasma proteins than atomoxetine.[A175669]
ABSORPTION The pharmacokinetic profile of atomoxetine is highly dependent on the genetic metabolizing state of CYP2D6 in the individual. Based on this, the reported bioavailability of atomoxetine can vary from 63-94% for extensive and poor metabolizers respectively. However, disregarding the CYP2D6 condition, atomoxetine is believed to present a very high intestinal permeability. The absorption of atomoxetine is dose-proportional and when a dose of 40 mg is administered, a maximal concentration of 350 ng/ml was reached in 1-2.5 hours with an AUC of 2 mcg.h/ml.[A175669] The absorption rate and bioavailability potential are not affected by the concomitant administration of food and hence, this medication can be taken with or without food.[A175750]
MOA Atomoxetine is known to be a potent and selective inhibitor of the norepinephrine transporter (NET)[A175723], which prevents cellular reuptake of norepinephrine throughout the brain, which is thought to improve the symptoms of ADHD. More recently, positron emission tomography (PET) imaging studies in rhesus monkeys have shown that atomoxetine also binds to the serotonin transporter (SERT)[A178111], and blocks the N-methyl-d-aspartate (NMDA) receptor [A18263], indicating a role for the glutamatergic system in the pathophysiology of ADHD.
HALF-LIFE The reported half-life depends on the CYP2D6 genetic polymorphisms of the individual and can range from 3 to 5.6 hours.[A175669]
INDICATION Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adults.
ROE Atomoxetine is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide, mainly in the urine (greater than 80% of the dose) and to a lesser extent in the feces (less than 17% of the dose). Only a small fraction (less than 3%) of the atomoxetine dose is excreted as unchanged atomoxetine, indicating extensive biotransformation.[F4639]
ABSORPTION The pharmacokinetic profile of atomoxetine is highly dependent on cytochrome P450 2D6 genetic polymorphisms of the individual [A175669]. A large fraction of the population (up to 10% of Caucasians and 2% of people of African descent and 1% of Asians) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. These individuals have reduced activity in this pathway resulting in 10-fold higher AUCs, 5-fold higher peak plasma concentrations, and slower elimination (plasma half-life of 21.6 hours) of atomoxetine compared with people with normal CYP2D6 activity.; ; Atomoxetine is rapidly absorbed after oral administration, with absolute bioavailability of about 63% in extensive metabolizers (EMs) and 94% in poor metabolizers (PMs). Mean maximal plasma concentrations (Cmax) are reached approximately 1 to 2 hours after dosing with a maximal concentration of 350 ng/ml with an AUC of 2 mcg.h/ml[A175669].;
DESCRIPTION Atomoxetine is primarily a norepinephrine (noradrenaline) reuptake inhibitor (NRI), with weak inhibitory effects on SERT (serotonin reuptake), and DAT (dopamine reuptake). (GtoPdb)
TOXICITY There is limited clinical trial experience with atomoxetine overdose. During postmarketing, there have been fatalities reported involving a mixed ingestion overdose of atomoxetine capsules and at least one other drug. There have been no reports of death involving overdose of atomoxetine capsules alone, including intentional overdoses at amounts up to 1400 mg. In some cases of overdose involving atomoxetine, seizures have been reported. The most commonly reported symptoms accompanying acute and chronic overdoses of atomoxetine capsules were gastrointestinal symptoms, somnolence, dizziness, tremor, and abnormal behavior. Hyperactivity and agitation have also been reported. Signs and symptoms consistent with mild to moderate sympathetic nervous system activation (e.g., tachycardia, blood pressure increased, mydriasis, dry mouth) have also been observed. Most events were mild to moderate. Less commonly, there have been reports of QT prolongation and mental changes, including disorientation and hallucinations. If symptoms of overdose are suspected, a Certified Poison Control Center should be consulted for up to date guidance and advice. Because atomoxetine is highly protein-bound, dialysis is not likely to be useful in the treatment of overdose.[F4639]
METABOLISM Atomoxetine undergoes biotransformation primarily through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway. People with reduced activity in the CYP2D6 pathway (also known as poor metabolizers or PMs) have higher plasma concentrations of atomoxetine compared with people with normal activity (also known as extensive metabolizers, or EMs). For PMs, the AUC of atomoxetine at steady-state is approximately 10-fold higher and Cmax is about 5-fold greater than for EMs. ; ; The major oxidative metabolite formed regardless of CYP2D6 status is 4-hydroxy-atomoxetine, which is rapidly glucuronidated. 4-Hydroxyatomoxetine is equipotent to atomoxetine as an inhibitor of the norepinephrine transporter, but circulates in plasma at much lower concentrations (1% of atomoxetine concentration in EMs and 0.1% of atomoxetine concentration in PMs). ; ; In individuals that lack CYP2D6 activity, 4-hydroxyatomoxetine is still the primary metabolite, but is formed by several other cytochrome P450 enzymes and at a slower rate. Another minor metabolite, N-Desmethyl-atomoxetine is formed by CYP2C19 and other cytochrome P450 enzymes, but has much less pharmacological activity than atomoxetine and lower plasma concentrations (5% of atomoxetine concentration in EMs and 45% of atomoxetine concentration in PMs).[F4639]
DESCRIPTION Highly potent and selective 5-HT uptake inhibitor (Tocris Bioactive Compound Library)
DESCRIPTION Potent, selective noradrenalin re-uptake inhibitor (Tocriscreen Total)
DESCRIPTION Atomoxetine is a selective inhibitor of noradrenaline reuptake. Atomoxetine was originally called tomoxetine but changed to avoid any potential confusion with tamoxifen that might lead to errors in dispensing the drug. It is a selective norepinephrine reuptake inhibitor with Ki values of 5, 77, and 1,451 nM for norepinephrine, serotonin, and dopamine transporters, respectively. Atomoxetine (0.1, 0.5, and 1 mg/kg) reduces premature responding, a measure of impulsivity, by rats in the 5-choice serial reaction time test (5CSRTT) in a dose-dependent manner. (BOC Sciences Bioactive Compounds)
Cell lines
0
Organisms
2
Compound Sets
29
Axon Medchem Screening Library
1297
BOC Sciences Bioactive Compounds
tomoxetine-cas-83015-26-3-item-78080
Cayman Chemical Bioactives
22248
ChEMBL Approved Drugs
CHEMBL1702
CHEMBL641
ChEMBL Drugs
CHEMBL1702
CHEMBL641
Drug Repurposing Hub
DrugBank
DB00289
DrugBank Approved Drugs
DB00289
DrugCentral
256
DrugCentral Approved Drugs
256
DrugMAP
DM5L6HI
DrugMAP Approved Drugs
DM5L6HI
EU-OPENSCREEN Bioactive Compound Library
EOS101440
Guide to Pharmacology
7118
LSP-MoA library (Laboratory of Systems Pharmacology)
CHEMBL641
Mcule NIBR MoA Box Subset
MCULE-6867007877
MedChem Express Bioactive Compound Library
HY-17385
NCATS Inxight Approved Drugs
ASW034S0B8
NIH Clinical Collections (NCC)
Novartis Chemogenetic Library (NIBR MoA Box)
NPC Screening Collection
Other bioactive compounds
Prestwick Chemical Library
ReFrame library
Selleckchem Bioactive Compound Library
atomoxetine-hydrochloride
TargetMol Bioactive Compound Library
T0869
The Spectrum Collection
Tocris Bioactive Compound Library
2011
Tocriscreen Total
External IDs
65
Properties
(calculated by RDKit )
Molecular Weight
255.16
Hydrogen Bond Acceptors
2
Hydrogen Bond Donors
1
Rotatable Bonds
6
Ring Count
2
Aromatic Ring Count
2
cLogP
3.72
TPSA
21.26
Fraction CSP3
0.29
Chiral centers
1.0
Largest ring
6.0
QED
0.85
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Pathway
GPCR/G protein
Neuroscience
Neuronal Signaling
Target
5-HT
DA transporter
Norepinephrine (NE) transporter
GRIN1, GRIN2A, GRIN2B, GRIN2C, GRIN2D, GRIN3A, GRIN3B, SLC6A2, SLC6A3, SLC6A4
NRI inhibitor
Adrenergic Receptor
5-HT Receptor
Primary Target
Adrenergic Transporters
MOA
Inhibitor
Norepinephrine Transporter (NET) Inhibitors
norepinephrine transporter inhibitor
Member status
member
Indication
attention-deficit/hyperactivity disorder (ADHD)
Source data