serotonin reuptake; norepinephrine reuptake

Duloxetine is a pretreat of norepinephrine reuptake and serotonin (5-HT). Duloxetine has a weaker inhibitory effect on dopamine reuptake when compared to its effects on 5-HT and norepinephrine reuptake. It also exhibits low binding affinity for other neurotransmitter receptors, such as opioid receptors, dopamine D2 receptors, adrenergic, muscarinic (nonselective), and histamine H1 receptors. More than 90% of duloxetine in human plasma is protein bound, according to in vitro research. A1-acid glycoprotein and albumin are the main targets of the binding[1].

Maximum plasma concentration (Cmax) of duloxetine ranges from about 47 ng/mL (40 mg twice-daily dose) to 110 ng/mL (80 mg twice-daily dose) about 6 hours after dosing. Duloxetine has an elimination half-life of roughly 10–12 hours and a distribution volume of about 1640 L. After a 60 mg single dose, the absolute oral bioavailability ranged from 30% to 80% on average in one study and from 19% to 71% on average in another. Duloxetine absorption is influenced by food and time of day; food and bedtime administration cause a 4-hour tmax delay[1].

Cell Viability Assay[2] Cells were seeded in 96-well plates at a density of 2 × 105 cells per well, grown for 24 h, and then treated with the drugs according to time-dependence or dose-dependence protocols. Each treatment was conducted in triplicate. After the drug treatments, the cell viability was assayed using a Cell Counting Kit-8 (CCK-8) according to the manufacturer’s instructions. CCK-8 uses the sensitive colorimetric WST-8 assay to determine the number of viable cells. WST-8 is a highly water-soluble tetrazolium salt, with the chemical designation of 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt

Duloxetine and α-Adrenergic Receptor Antagonists Administration[3] Duloxetine was dissolved in distilled water (D.W.). Different doses of duloxetine (10, 30, and 60 mg/kg) were administered (i.p.). To test which adrenergic receptor subtypes mediated the anti-allodynic effects of duloxetine in oxaliplatin-administered mice, antagonists were administered intrathecally 20 min prior to duloxetine treatments. Non-selective α-adrenergic antagonists (phentolamine, 20 μg), α1-adrenergic receptor antagonists (prazosin, 10 μg), and α2-adrenergic receptor antagonists (idazoxan, 10 μg) were administered in volumes of 5 μL. The dose of each antagonist was determined based on previously conducted studies showing the selective and effective antagonistic action against adrenergic receptor-mediated responses.[3]

Absorption, Distribution and Excretion
Duloxetine is incompletely absorbed with a mean bioavailability of 50% although there is wide variability in the range of 30-80%. The population absorption constant (ka) is 0.168 h-1.The molecule is susceptible to hydrolysis in acidic environments necessitating the use of an enteric coating to protect it during transit through the stomach. This creates a 2 hour lag time from administration to the start of absorption. The Tmax is 6 hours including the lag time. Administering duloxetine with food 3 hour delay in Tmax along with an 10% decrease in AUC. Similarly, administering the dose at bedtime produces a 4 hour delay and 18% decrease in AUC with a 29% reduction in Cmax. These are attributed to delayed gastric emptying in both cases but are not expected to impact therapy to a clinically significant degree.
About 70% of duloxetine is excreted in the urine mainly as conjugated metabolites. Another 20% is present in the feces as the parent drug, 4-hydroxy metabolite, and an uncharacterized metabolite. Biliary secretion is thought to play a role due to timeline of fecal excretion exceeding the time expected of normal GI transit.
Apparent Vd of 1620-1800 L. Duloxetine crosses the blood-brain barrier and collects in the cerebral cortex at a higher concentration than the plasma.
There is a large degree of interindividual variation reported in the clearance of duloxetine with values ranging from 57-114 L/h. Steady state concentrations have still been shown to be dose proportional with a doubling of dose from 30 to 60 mg and from 60 to 120 mg producing 2.3 and 2.6 times the Css respectively.
Many additional metabolites have been identified in urine, some representing only minor pathways of elimination. Only trace (<1% of the dose) amounts of unchanged duloxetine are present in the urine. Most (about 70%) of the duloxetine dose appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces. Duloxetine undergoes extensive metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine.
Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic range. Steady-state plasma concentrations are typically achieved after 3 days of dosing. Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP1A2 and CYP2D6.
Orally administered duloxetine hydrochloride is well absorbed. There is a median 2 hour lag until absorption begins (Tlag), with maximal plasma concentrations (Cmax) of duloxetine occurring 6 hours post dose. Food does not affect the Cmax of duloxetine, but delays the time to reach peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (AUC) by about 10%. There is a 3 hour delay in absorption and a one-third increase in apparent clearance of duloxetine after an evening dose as compared to a morning dose. The apparent volume of distribution averages about 1640 L. Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and a1-acid glycoprotein. The interaction between duloxetine and other highly protein bound drugs has not been fully evaluated. Plasma protein binding of duloxetine is not affected by renal or hepatic impairment.

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Metabolism / Metabolites
Duloxetine is extensively metabolized primarily by CYP1A2 and CYP2D6 with the former being the greater contributor. It is hydroxylated at the 4, 5, or 6 positions on the naphthalene ring with the 4-hydroxy metabolite proceeding directly to a glucuronide conjugate while the 5 and 6-hydroxy metabolites proceed through a catechol and a 5-hydroxy, 6-methoxy intermediate before undergoing glucuronide or sulfate conjugation. CYP2C9 is known to be a minor contributor to the 5-hydroxy metabolite. Another uncharacterized metabolite is known to be excreted in the feces but comprises <5% of the total excreted drug. Many other metabolites exist but have not been identified due their low contribution to the overall profile of duloxetine and lack of clinical significance.
Biotransformation and disposition of duloxetine in humans have been determined following oral administration of (14C)-labeled duloxetine. Duloxetine comprises about 3% of the total radiolabeled material in the plasma, indicating that it undergoes extensive metabolism to numerous metabolites. The major biotransformation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP1A2 and CYP2D6 catalyze the oxidation of the naphthyl ring in vitro. Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate.
Duloxetine has known human metabolites that include 5-((S)-3-Methylamino-1-thiophen-2-yl-propoxy)-naphthalen-2-ol, 5-Hydroxyduloxetine, and 4-Hydroxyduloxetine.
The major biotransformation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP2D6 and CYP1A2 catalyze the oxidation of the naphthyl ring in vitro. Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate. The major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine.
Route of Elimination: Many additional metabolites have been identified in urine, some representing only minor pathways of elimination. Most (about 70%) of the duloxetine dose appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces.
Half Life: 12 hours (range 8-17 hours)

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Biological Half-Life
Mean of 12 h with a range of 8-17.
Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic range.

Toxicity Summary
IDENTIFICATION AND USE: Duloxetine hydrochloride is used for the acute management of generalized anxiety disorder in adults, the management of neuropathic pain associated with diabetic peripheral neuropathy in adults, the management of fibromyalgia in adults, the management of moderate to severe stress urinary incontinence (SUI) in women, and the acute and maintenance treatment of major depressive disorder in adults. HUMAN EXPOSURE AND TOXICITY: Possible risk of severe hepatic toxicity; elevated serum transaminase concentrations, sometimes requiring discontinuance of duloxetine, have been reported. In postmarketing experience, fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine only, at doses as low as 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting. A higher proportion of patients reporting discontinuation-emergent adverse events were seen with 120 mg/day duloxetine compared with lower doses. For doses between 40 and 120 mg/day duloxetine the proportion of patients reporting at least one discontinuation-emergent adverse event differed significantly from placebo. Extended treatment with duloxetine beyond 8-9 weeks did not appear to be associated with an increased incidence or severity of discontinuation-emergent adverse events. Abrupt discontinuation of duloxetine is associated with a discontinuation-emergent adverse event profile similar to that seen with other selective serotonin reuptake inhibitor (SSRI) and selective serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants ANIMAL STUDIES: Duloxetine was administered in the diet to mice for 2 years. In female mice receiving duloxetine at 140 mg/kg/day (6 times the maximum recommended human dose (MRHD) of 120 mg/day on a mg/ sq m basis), there was an increased incidence of hepatocellular adenomas and carcinomas. The no-effect dose was 50 mg/kg/day (2 times the MRHD). Tumor incidence was not increased in male mice receiving duloxetine at doses up to 100 mg/kg/day (4 times the MRHD). Duloxetine administered orally to either male or female rats prior to and throughout mating at doses up to 45 mg/kg/day (4 times the MRHD) did not alter mating or fertility. When duloxetine was administered orally to pregnant rats throughout gestation and lactation, the survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were decreased at a dose of 30 mg/kg/day (5 times the MRHD and 2 times the human dose of 120 mg/day on a mg/sq m basis); the no-effect dose was 10 mg/kg/day. Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups following maternal exposure to 30 mg/kg/day. Post-weaning growth and reproductive performance of the progeny were not affected adversely by maternal duloxetine treatment. Duloxetine was not mutagenic in the bacterial reverse mutation assay (Ames test), and not clastogenic in an in vivo chromosomal aberration test in mouse bone marrow cells. Additionally, it was not genotoxic in an in vitro mammalian forward gene mutation assay in mouse lymphoma cells or in an in vitro unscheduled DNA assay in rat hepatocytes, and did not induce in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells.
Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors. The antidepressant and pain inhibitory actions of duloxetine are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS. The mechanism of action of duloxetine in SUI has not been determined, but is thought to be associated with the potentiation of serotonin and norepinephrine activity in the spinal cord, which increases urethral closure forces and thereby reduces involuntary urine loss.

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Toxicity Data
Oral, rat LD₅₀: 491 mg/kg for males and 279 mg/kg for females (A308).

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Interactions
Duloxetine is an inhibitor of the CYP1A2 isoform in in vitro studies, and in two clinical studies the average (90% confidence interval) increase in theophylline AUC was 7% (1%-15%) and 20% (13%-27%) when co-administered with duloxetine (60 mg twice daily).
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are co-administered with warfarin. Concomitant administration of warfarin (2-9 mg once daily) under steady state conditions with duloxetine 60 or 120 mg once daily for up to 14 days in healthy subjects (n=15) did not significantly change INR from baseline (mean INR changes ranged from 0.05 to +0.07). The total warfarin (protein bound plus free drug) pharmacokinetics (AUCt,ss, Cmax,ss or tmax,ss) for both R- and S-warfarin were not altered by duloxetine. Because of the potential effect of duloxetine on platelets, patients receiving warfarin therapy should be carefully monitored when duloxetine is initiated or discontinued.
Concomitant administration of duloxetine 40 mg twice daily with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to CYP2D6 poor metabolizer subjects (n=14) resulted in a 6-fold increase in duloxetine AUC and Cmax.
Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) increased the concentration of duloxetine AUC by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine).
When duloxetine 60 mg was co-administered with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to male subjects (n=14) duloxetine AUC was increased approximately 6-fold, the Cmax was increased about 2.5-fold, and duloxetine t1/2 was increased approximately 3-fold. Other drugs that inhibit CYP1A2 metabolism include cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin.

[1]. Clin Pharmacokinet . 2011 May;50(5):281-94.

[2]. Duloxetine-Induced Neural Cell Death and Promoted Neurite Outgrowth in N2a Cells. Neurotox Res. 2020 Dec;38(4):859-870.
[3]. Duloxetine Protects against Oxaliplatin-Induced Neuropathic Pain and Spinal Neuron Hyperexcitability in Rodents. Int J Mol Sci . 2017 Dec 5;18(12):2626.

Therapeutic Uses
Adrenergic Uptake Inhibitors; Analgesics; Antidepressive Agents; Dopamine Uptake Inhibitors; Serotonin Uptake Inhibitors
Duloxetine hydrochloride is used for the acute and maintenance treatment of major depressive disorder in adults.
Duloxetine has been used for the management of moderate to severe stress urinary incontinence (SUI) in women.
Duloxetine hydrochloride is used for the management of fibromyalgia in adults.
For more Therapeutic Uses (Complete) data for DULOXETINE (6 total), please visit the HSDB record page.

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Drug Warnings
/BOXED WARNING/ WARNING: SUICIDAL THOUGHTS AND BEHAVIORS: Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber.
Pregnancy Category C. Some neonates exposed to selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) or selective serotonin-reuptake inhibitors late in the third trimester of pregnancy have developed complications that have sometimes been severe and required prolonged hospitalization, respiratory support, enteral nutrition, and other forms of supportive care in special-care nurseries. Such complications can arise immediately upon delivery and usually last several days or up to 2-4 weeks. Clinical findings reported to date in the neonates have included respiratory distress, cyanosis, apnea, seizures, temperature instability or fever, feeding difficulty, dehydration, excessive weight loss, vomiting, hypoglycemia, hypotonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, reduced or lack of reaction to pain stimuli, and constant crying. These clinical features appear to be consistent with either a direct toxic effect of the SNRI or selective serotonin-reuptake inhibitor or, possibly, a drug withdrawal syndrome. It should be noted that, in some cases, the clinical picture was consistent with serotonin syndrome (see Drug Interactions: Drugs Associated with Serotonin Syndrome, in Fluoxetine Hydrochloride 28:16.04.20). When treating a pregnant woman with duloxetine during the third trimester of pregnancy, the clinician should carefully consider the potential risks and benefits of such therapy. Consideration may be given to cautiously tapering duloxetine therapy in the third trimester prior to delivery if the drug is administered during pregnancy.
Potentially life-threatening serotonin syndrome reported with selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), including duloxetine, or selective serotonin-reuptake inhibitors (SSRIs), particularly with concurrent administration of other serotonergic drugs (e.g., serotonin [5-hydroxytryptamine; 5-HT] type 1 receptor agonists ["triptans"]) or drugs that impair serotonin metabolism (e.g., monoamine oxidase [MAO] inhibitors). Symptoms of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea). Concurrent therapy with MAO inhibitors used for treatment of depression is contraindicated. (See Drug Interactions: Monoamine Oxidase Inhibitors.) If concurrent therapy with duloxetine and a 5-HT1 receptor agonist is clinically warranted, the patient should be observed carefully, particularly during initiation of therapy, when dosage is increased, or when another serotonergic agent is initiated. Concomitant use of duloxetine and serotonin precursors (e.g., tryptophan) is not recommended.
Hepatic failure, sometimes fatal, has been reported in duloxetine-treated patients.The cases presented as hepatitis accompanied by abdominal pain, hepatomegaly, and markedly elevated serum transaminase concentrations (more than 20 times the upper limit of normal) with or without jaundice, reflecting a mixed or hepatocellular pattern of hepatic injury. Duloxetine should be discontinued in any patient who develops jaundice or other evidence of clinically important hepatic dysfunction; therapy should not be resumed unless another cause for the hepatic dysfunction can be established.
For more Drug Warnings (Complete) data for DULOXETINE (18 total), please visit the HSDB record page.

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Pharmacodynamics
Duloxetine, through increasing serotonin and norepinephrine concentrations in Onuf's nucleus, enhances glutamatergic activation of the pudendal motor nerve which innervates the external urethral sphinter. This enhanced signaling allows for stronger contraction. Increased contraction of this sphincter increases the pressure needed to produce an incontinence episode in stress urinary incontinence. Duloxetine has been shown to improve Patient Global Impression of Improvement and Incontinence Quality of Life scores. It has also been shown to reduce the median incontinence episode frequency at doses of 40 and 80 mg. Action at the dorsal horn of the spinal cord allows duloxetine to strengthen the the serotonergic and adrenergic pathways involved in descending inhibition of pain. This results in an increased threshold of activation necessary to transmit painful stimuli to the brain and effective relief of pain, particularly in neuropathic pain. Pain relief has been noted in a variety of painful conditions including diabetic peripheral neuropathy, fibromyalgia, and osteoarthritis using a range of pain assessment surveys. While duloxetine has been shown to be effective in both animal models of mood disorders and in clinical trials for the treatment of these disorders in humans, the broad scope of its pharmacodynamic effects on mood regulation in the brain has yet to be explained. Increased blood pressure is a common side effect with duloxetine due to vasoconstriction mediated by the intended increase in norepinephrine signaling.

C18H19NOS

297.416

297.12

116539-59-4

Duloxetine hydrochloride; 136434-34-9; Duloxetine-d7; 919514-01-5; (±)-Duloxetine hydrochloride; 947316-47-4; Duloxetine metabolite Para-Naphthol Duloxetine; 949095-98-1

60835

Typically exists as solid at room temperature

1.2±0.1 g/cm3

466.2±40.0 °C at 760 mmHg

235.7±27.3 °C

0.0±1.2 mmHg at 25°C

1.628

3.73

1

3

6

21

312

1

CNCC[C@H](OC1=CC=CC2=C1C=CC=C2)C3=CC=CS3

ZEUITGRIYCTCEM-KRWDZBQOSA-N

InChI=1S/C18H19NOS/c1-19-12-11-17(18-10-5-13-21-18)20-16-9-4-7-14-6-2-3-8-15(14)16/h2-10,13,17,19H,11-12H2,1H3/t17-/m0/s1

(3S)-N-methyl-3-naphthalen-1-yloxy-3-thiophen-2-ylpropan-1-amine

LY248686; LY-227942; LY-248686; LY 227942; (S)-Duloxetine; (S)-Duloxetine; Yentreve; Cymbalta; (S)-N-Methyl-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propan-1-amine; LY 248686; HSDB 7368; Duloxetine

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.)