Absorption, Distribution and Excretion
Veroxazine is rapidly absorbed after oral administration. The relative bioavailability of extended-release vertoxazine formulations compared to immediate-release formulations is approximately 88%. With a once-daily dose range of 100 mg to 600 mg, the Cmax and AUC of vertoxazine increase proportionally. Cmax ranges from 540 to 1600 ng/mL. After a single 200 mg dose, the median Tmax is approximately 5 hours, ranging from 3 to 9 hours. Steady state is reached after two days of once-daily administration, with no drug accumulation observed. High-fat meals can reduce Cmax and AUC by approximately 9% and 8%, respectively, and delay Tmax by 2 hours. Veroxazine is primarily excreted via the kidneys. Following administration of radiolabeled vertoxazine, 90% of the dose is excreted in the urine within 24 hours of administration. Less than 1% of the dose is excreted in the feces. Approximately 12-15% of the total drug is excreted unchanged.
The volume of distribution after intravenous administration was 0.73 ± 0.28 L/kg.
The clearance after intravenous administration was 124 ± 11 mL/h/kg.
Metabolism/Metabolites
Veloxazine is 5-hydroxylated by CYP2D6 to form 5-hydroxyviloxazine. This metabolite can be glucuroninated by UGT1A9 and UGT2B15 to form 5-hydroxyviloxazine glucuronide, the major metabolite detected in plasma. Veloxazine can also be glucuroninated to form viloxazine N-carbamoyl glucuronide.
Biological Half-Life
The mean (± SD) half-life of viloxazine is 7.02 (± 4.74) hours.

Hepatotoxicity
In four placebo-controlled trials of velocxazine in children with attention deficit hyperactivity disorder (ADHD), 5% to 10% of participants experienced mild elevations in serum transaminases, but less than 1% experienced elevations exceeding twice the upper limit of normal. No clinically significant liver injury or elevated serum transaminases with jaundice were observed with velocxazine in pre-registration trials. Since its approval in Europe for the treatment of depression over 30 years ago and in the United States for the treatment of ADHD in 2021, no clinically significant liver injury caused by velocxazine has been reported in the literature. Furthermore, no adverse liver events were mentioned in the efficacy and safety summaries of velocxazine. However, long-term clinical experience with velocxazine in children is limited, and other selective serotonin and norepinephrine reuptake inhibitors (such as atormoxetine) have also been associated with rare cases of clinically significant liver injury. Probability Score: E (Unlikely a cause of acute liver injury with jaundice).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
Currently, there are no reported studies on the use of vecloxacillin during lactation. If a mother of an older infant needs to take vecloxacillin, this is not a reason to stop breastfeeding, but until more data is available, it may be preferable to choose other medications, especially when breastfeeding newborns or premature infants.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Protein binding
In the range of plasma concentrations from 0.5 mcg/mL to 10 mcg/mL, vecloxacillin binds to human plasma proteins at a rate of 76-82%.

2-[(2-ethoxyphenoxy)methyl]morpholine is an aromatic ether. Veroxazine is a selective norepinephrine reuptake inhibitor. For decades, immediate-release formulations of vertoxazine have been used as antidepressants in Europe. It was first approved in the UK in 1974; however, the immediate-release formulation was discontinued for commercial reasons unrelated to drug safety and efficacy. In the US, vertoxazine was granted orphan drug designation in 1984 under the brand name CATATROL: although the product was intended to treat cataplexy and narcolepsy, it was never approved for these indications. In April 2021, extended-release formulations of vertoxazine, branded QELBREE, received FDA approval for the treatment of attention deficit hyperactivity disorder (ADHD). Veroxazine is a norepinephrine reuptake inhibitor. Veroxazine's mechanism of action is as a norepinephrine reuptake inhibitor, a cytochrome P450 1A2 inhibitor, a cytochrome P450 2D6 inhibitor, a cytochrome P450 3A4 inhibitor, and a cytochrome P450 2B6 inhibitor. Veroxazine is a selective norepinephrine reuptake inhibitor used to treat attention deficit hyperactivity disorder (ADHD) in children. Rare and mild elevations in serum enzymes have been observed during vertoxazine treatment, but no clinically significant liver damage has been observed. It is a morpholine derivative used as an antidepressant. Its mechanism of action is similar to imipramine. See also: Veroxazine hydrochloride (active ingredient). Drug Indications Veroxazine is a selective norepinephrine reuptake inhibitor indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in adults and children aged 6 years and older.

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Mechanism of Action
Attention deficit hyperactivity disorder (ADHD) is a common childhood neurodevelopmental disorder characterized by inattention and hyperactivity. Current literature suggests that the pathophysiological mechanism of ADHD is related to neurotransmitter imbalances, particularly dopamine (DA) and norepinephrine (NE). The mechanism of action of viloxazine is not fully elucidated; however, it is believed to act by modulating the monoaminergic neurotransmitter system. Velloxazine is a selective, moderate-potency norepinephrine reuptake inhibitor that binds to norepinephrine transporters, inhibiting norepinephrine reuptake. Therefore, it can increase extracellular norepinephrine levels in multiple brain regions. Velloxazine can enhance serotonergic effects: studies have shown that it can enhance neuronal sensitivity to serotonin and increase intrabrain serotonin levels. In vitro experiments have shown that viloxazine is an antagonist of the 5-HT2B receptor and an agonist of the 5-HT2C receptor.
5-HT2B receptors expressed on GABAergic interneurons are involved in the sustained inhibitory control of serotonergic neurons innervating the medial prefrontal cortex. Therefore, antagonism of 5-HT2B receptors may lead to deinhibition and increased serotonin release in specific brain regions. Evidence in the literature regarding velonoxazine's direct or indirect effects on increasing brain dopamine levels is inconsistent. For example, norepinephrine transporters are also involved in dopamine reuptake in the prefrontal cortex, while stimulation of 5-HT2C receptors can promote dopamine release and enhance dopaminergic transmission in the brain. Since dopamine dysregulation in the prefrontal cortex and amygdala is associated with the pathophysiological mechanisms of attention deficit hyperactivity disorder (ADHD), the effect of velonoxazine on dopamine levels may contribute to the establishment of its mechanism of action. However, there is currently insufficient evidence to draw this conclusion. The effect of velonoxazine on dopamine in the nucleus accumbens is negligible and does not pose a risk of abuse.

C13H19NO3

237.136

46817-91-8

Viloxazine hydrochloride;35604-67-2

5666

Colorless to light yellow oil

1.061 g/cm3

350.5ºC at 760 mmHg

185-186ºC

144.3ºC

1.499

1.781

1

4

5

17

213

0

C(OC1C=CC=CC=1OCC1CNCCO1)C

YWPHCCPCQOJSGZ-UHFFFAOYSA-N

InChI=1S/C13H19NO3/c1-2-15-12-5-3-4-6-13(12)17-10-11-9-14-7-8-16-11/h3-6,11,14H,2,7-10H2,1H3

2-[(2-ethoxyphenoxy)methyl]morpholine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)