The binding of the serotonin transporter radioligand [3H]-paroxetine to cell membranes transfected with the human 5-HT transporter is dose-dependently inhibited by venlafaxine (Wy 45030), with a Ki of 2.48 μM. With a Ki of 82 nM, venlafaxine prevents the NE transporter ligand [3H]-nisoxetine from attaching to the membrane of a transfected human NE transporter [1]. With ED50 values of 2 and 54 mg/kg, respectively, venlafaxine inhibits the binding to the rat 5-HT transporter and the NE transporter in vitro[1].

In the rat hypothalamus, venlafaxine (Wy 45030; 10-100 mg/kg; IP) dose-dependently prevents the 6-OHDA-induced reduction of norepinephrine levels [1].

Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rats, body weight 180-230 grams [1]
Doses: 10, 30, 100 mg/kg
Route of Administration: IP; para-chloramphetamine hydrochloride (p-CA; 10 mg/kg; intraperitoneal (ip) injection ) Results one hour before: dose-dependently blocked 6-OHDA-induced depletion of norepinephrine levels in the rat hypothalamus (intracerebroventricular; 50 μg/rat; one hour later)), ED50 values were 12 and 94 mg/kg.

Absorption, Distribution and Excretion
Venlafaxine is well absorbed after oral administration, with an absolute bioavailability of approximately 45%. Mass balance studies indicate that at least 92% of venlafaxine is absorbed after a single oral dose. After twice-daily oral administration of the immediate-release formulation, the peak plasma concentration (Cmax) is 150 ng/mL, and the time to peak concentration (Tmax) is 5.5 hours. The Cmax and Tmax of once-daily oral administration of venlafaxine (ODV) are 260 ng/mL and 9 hours, respectively. The extended-release formulation of venlafaxine is absorbed more slowly, but to the same extent as the immediate-release formulation. After once-daily oral administration of the extended-release formulation, the peak plasma concentration (Cmax) is 225 ng/mL, and the time to peak concentration (Tmax) is 2 hours. The Cmax and Tmax of once-daily oral administration of venlafaxine (ODV) are 290 ng/mL and 3 hours, respectively. Food does not affect the bioavailability of venlafaxine and its active metabolite O-desmethylvenlafaxine (ODV). Approximately 87% of the venlafaxine dose is excreted in the urine within 48 hours as unchanged venlafaxine (5%), unbound ODV (29%), bound ODV (26%), or other trace amounts of inactive metabolites (27%). The apparent volume of distribution of venlafaxine at steady state is 7.5 ± 3.7 L/kg, and the ODV is 5.7 ± 1.8 L/kg. The mean plasma apparent clearance ± standard deviation of venlafaxine at steady state is 1.3 ± 0.6 L/h/kg, and the ODV is 0.4 ± 0.2 L/h/kg. Venlafaxine is well absorbed…based on mass balance studies, the absorption rate of venlafaxine after at least a single oral dose is 92%. The absolute bioavailability of venlafaxine is approximately 45%. Steady-state plasma concentrations of venlafaxine and O-desmethylvenlafaxine are reached within 3 days after multiple oral doses. Venlafaxine and O-desmethylvenlafaxine exhibit linear pharmacokinetics within a dose range of 75 to 450 mg/day. The mean steady-state plasma clearances of venlafaxine and O-desmethylvenlafaxine were 1.3 ± 0.6 L/hr/kg and 0.4 ± 0.2 L/hr/kg, respectively; the apparent elimination half-lives were 5 ± 2 hours and 11 ± 2 hours, respectively; and the apparent (steady-state) volumes of distribution were 7.5 ± 3.7 L/kg and 5.7 ± 1.8 L/kg, respectively. Venlafaxine and O-desmethylvenlafaxine showed very low binding to plasma proteins at therapeutic concentrations (27% and 30%, respectively). Approximately 87% of the venlafaxine dose was excreted in the urine within 48 hours as unchanged venlafaxine (5%), unbound O-desmethylvenlafaxine (29%), bound O-desmethylvenlafaxine (26%), or other trace amounts of inactive metabolites (27%). Therefore, renal excretion is the primary route of excretion for venlafaxine and its metabolites. Venlafaxine is a unique antidepressant… The pharmacokinetics and relative bioavailability of venlafaxine were evaluated after oral administration in healthy volunteers. In a two-period randomized crossover study, the bioavailability of 50 mg venlafaxine tablets relative to solution was determined. The rate of absorption in the gastrointestinal tract was assessed by time to peak plasma concentration (tmax), model-based first-order absorption rate constant calculations, and model-based non-model mean residence time calculations. The extent of absorption was assessed by peak plasma concentration (Cmax) and area under the concentration-time curve (AUC). No statistically significant differences were observed between the two formulations in terms of absorption rate and extent of absorption. Similarly, there were no significant differences in the systemic concentrations of the active O-demethyl metabolite after administration of the two venlafaxine formulations. AUC ratios indicated that the relative bioavailability of the parent drug and metabolite formulations, compared to solution, was approximately 98% and 92%, respectively. Another study investigated the effect of food on the absorption of 50 mg venlafaxine tablets. Consuming a standard, medium-fat breakfast immediately before taking the medication will delay the tmax of venlafaxine, but will not affect Cmax or AUC. Therefore, venlafaxine tablets are bioequivalent to the oral solution, and the presence of food appears to decrease the absorption rate of venlafaxine tablets, but will not affect the extent of absorption. For more complete data on the absorption, distribution, and excretion of venlafaxine (8 of these), please visit the HSDB record page.

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Metabolism/Metabolites
After absorption, venlafaxine undergoes extensive first-pass metabolism in the liver. It primarily generates its active metabolite, O-demethylvenlafaxine (ODV), via CYP2D6-mediated demethylation. Venlafaxine can also generate N-demethylvenlafaxine (NDV) via CYP2C9, CYP2C19, and CYP3A4-mediated N-demethylation, but this is a minor metabolic pathway. ODV and NDV are further metabolized via CYP2C19, CYP2D6, and/or CYP3A4 to N,O-didesmethylvenlafaxine (NODV). NODV can be further metabolized to N,N,O-tridesmethylvenlafaxine, which may subsequently undergo glucuronidation. After absorption, venlafaxine undergoes extensive first-pass metabolism in the liver, primarily to O-desmethylvenlafaxine, but also to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites. In vitro studies have shown that the formation of O-desmethylvenlafaxine is catalyzed by CYP2D6; a clinical study confirmed this, showing that patients with low CYP2D6 levels ("patients with low metabolic capacity") had higher venlafaxine levels and lower O-desmethylvenlafaxine levels compared to patients with normal CYP2D6 levels ("patients with high metabolic capacity"). However, differences in CYP2D6 metabolic capacity between individuals with weak and strong metabolism are not expected to be clinically significant, as the total amounts of venlafaxine and O-desmethylvenlafaxine are similar in both groups, and venlafaxine and O-desmethylvenlafaxine are pharmacologically comparable in activity and potency. This study investigated the in vitro bioconversion of venlafaxine (VF) to its two major metabolites, O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV), using human liver microsomes and microsomes containing single human cytochromes from cDNA-transfected human lymphoblasts. VF was co-incubated with selective cytochrome P450 (CYP) inhibitors and several selective serotonin reuptake inhibitors (SSRIs) to assess their inhibitory effects on VF metabolism. The rate of ODV production after incubation with human microsomes conformed to Michaelis-Menten kinetics for single-enzyme-mediated substrate inhibition. The mean parameters determined by nonlinear regression analysis were: Vmax = 0.36 nmol/min/mg protein, Km = 41 μM, and Ks = 22901 μM (Ks represents a constant reflecting the degree of substrate inhibition). Quinidine (QUI) was a potent inhibitor of ODV generation with a Ki value of 0.04 μM; paroxetine (PX) was the most potent selective serotonin reuptake inhibitor (SSRI) for inhibiting ODV generation with a mean Ki value of 0.17 μM. Studies using expressed cytochromes showed that ODV is generated by CYP2C9, CYP2C19, and CYP2D6. CYP2D6 was dominant, with the lowest Km value (23.2 μM) and the highest intrinsic clearance (Vmax/Km ratio). No single model suitable for NDV generation was found for all four liver samples. The parameters determined using a single-enzyme model were: Vmax = 2.14 nmol/min/mg protein and Km = 2504 μM. Ketoconazole is a potent inhibitor of NDV production, but its inhibitory activity is less than that of pure 3A substrates. A polyclonal rabbit antibody targeting rat liver CYP3A1 also reduced NDV production by 42%. Studies using expressed cytochromes showed that NDV is generated by CYP2C9, -2C19, and -3A4. CYP2C19 exhibited the highest intrinsic clearance, while CYP3A4 showed the lowest. However, the high abundance of 3A isoenzymes in vivo highlights the importance of this cytochrome. Fluvoxamine (FX) at a concentration of 20 μM reduced NDV production by 46%, consistent with FX's ability to inhibit CYP3A, 2C9, and 2C19. These results are consistent with previous studies demonstrating that CYP2D6 and CYP3A4 play important roles in ODV and NDV production, respectively. Furthermore, we found that several other CYPs also play important roles in the biotransformation of VF. In a patient with both phenotype and genotype of extensive CYP2D6 metabolizer, we detected abnormally elevated trough concentrations of venlafaxine on three separate occasions. This patient was taking 450 mg of venlafaxine daily in addition to several other medications. In the first blood sample, the concentrations of venlafaxine and O-desmethylvenlafaxine were 1.54 mg/L and 0.60 mg/L, respectively, with an abnormally high venlafaxine/O-desmethylvenlafaxine ratio. This suggests impaired metabolism of venlafaxine to O-desmethylvenlafaxine, likely due to metabolic interactions with mianserin (240 mg/day) and propranolol (40 mg/day). The (S)-venlafaxine concentration measured in this blood sample was almost twice that of (R)-venlafaxine ((S)/(R) ratio 1.94). At the second blood draw, the addition of the potent CYP2D6 inhibitor thioridazine (260 mg/day) further increased venlafaxine concentration (2.76 mg/L), while decreasing O-desmethylvenlafaxine concentration (0.22 mg/L). The decrease in the (S)/(R)-venlafaxine ratio (-20%) suggests that, under high concentrations of venlafaxine, the enzyme involved in O-demethylation of venlafaxine may exhibit stereoselectivity for the (R)-enantiomer. At the third blood draw, after discontinuation of thioridazine, the concentrations of venlafaxine and O-desmethylvenlafaxine were similar to those measured at the first blood draw. This case report demonstrates the crucial importance of investigating the impact of inherited or acquired metabolic defects on the pharmacokinetics of venlafaxine. Approximately 87% of the venlafaxine dose is excreted in the urine within 48 hours as unchanged venlafaxine (5%), unbound O-desmethylvenlafaxine (29%), bound O-desmethylvenlafaxine (26%), or other small amounts of inactive metabolites (27%). Therefore, renal excretion is the primary route of excretion for venlafaxine and its metabolites. Venlafaxine undergoes extensive first-pass metabolism in the liver, producing its major active metabolite ODV and two less active minor metabolites, N-desmethylvenlafaxine and N,O-didesmethylvenlafaxine. ODV formation is catalyzed by cytochrome P450 (CYP) 2D6, while N-demethylation is catalyzed by CYP3A4, 2C19, and 2C9. ODV possesses antidepressant activity comparable to venlafaxine. Excretion pathway: The primary route of excretion for venlafaxine and its metabolites is renal excretion. Approximately 87% of the venlafaxine dose is excreted in the urine within 48 hours, in the form of unchanged venlafaxine (5%), unbound ODV (29%), bound ODV (26%), or other trace amounts of inactive metabolites (27%).
Half-life: 5 hours
Biological half-life
The apparent elimination half-life of venlafaxine is 5 ± 2 hours, and the apparent elimination half-life of ODV is 11 ± 2 hours.
The apparent elimination half-lives of venlafaxine and O-desmethylvenlafaxine are 5 ± 2 hours and 11 ± 2 hours, respectively.

Toxicity Summary
The exact mechanism of action of venlafaxine is unclear, but it appears to be related to its enhancement of neurotransmitter activity in the central nervous system. Venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), inhibit the reuptake of serotonin and norepinephrine, with a stronger inhibitory effect on 5-HT reuptake than on NE reuptake. Both venlafaxine and its metabolite ODV have weak inhibitory effects on dopamine reuptake, but unlike tricyclic antidepressants, and similar to selective serotonin reuptake inhibitors (SSRIs), they have no activity against histaminergic receptors, muscarinic receptors, or α1-adrenergic receptors. Interactions Although venlafaxine has not been shown to exacerbate alcohol-induced mental and motor skill impairments, patients should still be advised to avoid alcohol consumption while taking venlafaxine. A 25-year-old white woman with chronic depression was treated with venlafaxine 150 mg/day and tramipram 50 mg/day. Eleven days after the tramipram dose was increased to 100 mg/day, she was hospitalized for a seizure suggestive of secondary generalized tonic-clonic seizures. EEG showed a pathological pattern including multiple generalized epileptiform discharges. Both antidepressants were discontinued due to suspected drug-induced seizures. After discontinuation of the antidepressants, the patient's symptoms resolved, and she remained seizure-free during a subsequent 12-month follow-up period. No other possible causes of seizures were identified. Both venlafaxine and tramipram are associated with seizures, primarily occurring after overdose. No cases of seizures induced by therapeutic doses of venlafaxine have been reported in the literature. We hypothesize that pharmacodynamic or pharmacokinetic drug interactions involving the CYP2D6 isoenzyme between venlafaxine and tramipram may play a role in inducing seizures.
A patient developed neuroleptic malignancy after receiving a single dose of venlafaxine in combination with trifluoperazine. The dopamine inhibition caused by a single dose of venlafaxine may have enhanced the dopamine receptor inhibition of trifluoperazine.
In a steady-state study of 18 healthy subjects, concomitant administration of cimetidine and venlafaxine inhibited the first-pass metabolism of venlafaxine. Oral clearance of venlafaxine decreased by approximately 43%, while drug exposure (AUC) and maximum concentration (Cmax) increased by approximately 60%. However, the combination of cimetidine and O-desmethylvenlafaxine had no significant effect on the pharmacokinetics of O-desmethylvenlafaxine, whose circulating levels are much higher than those of venlafaxine alone. The overall pharmacological activity of venlafaxine in combination with O-desmethylvenlafaxine is expected to increase only slightly, and no dose adjustment is required in most healthy adults. However, the interaction between venlafaxine and cimetidine is unclear and may be more significant in patients with a history of hypertension, elderly patients, or patients with hepatic impairment. Therefore, caution is advised when using this medication in these patients. For more complete data on venlafaxine drug interactions (24 items in total), please visit the HSDB record page.

[1]. Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology. 2001 Dec;25(6):871-80.

[2]. Postmortem tissue concentrations of venlafaxine. Forensic Sci Int. 2001 Sep 15;121(1-2):70-5.

Therapeutic Uses

Second-generation antidepressant; serotonin reuptake inhibitor
Venlafaxine hydrochloride is used to treat major depressive disorder. /US product label includes/
Venlafaxine hydrochloride is used to treat generalized anxiety disorder. /US product label includes/
Venlafaxine hydrochloride is used to treat social phobia (social anxiety disorder). /US product label includes/
For more complete data on the therapeutic uses of venlafaxine (of 10), please visit the HSDB record page.

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Drug Warnings
/Black Box Warning/ Warning: Suicidal ideation and behavior. Short-term studies have shown that antidepressants increase the risk of suicidal ideation and behavior in children, adolescents, and young adults. These studies did not show an increased risk of suicidal ideation and behavior in patients aged 24 years and older; conversely, antidepressants decreased the risk of suicidal ideation and behavior in patients aged 65 years and older. Patients of all ages should be closely monitored for worsening clinical symptoms and the occurrence of suicidal ideation and behavior when starting antidepressant therapy. Patients' families and caregivers should be informed of the need for close monitoring and communication with the prescribing physician. The U.S. Food and Drug Administration (FDA) recommends that all patients receiving antidepressant treatment for any indication should be appropriately monitored for worsening clinical symptoms, suicidal tendencies, and unusual behavioral changes, especially during the initial months of treatment and dose adjustments. Families and caregivers of patients with major depressive disorder or other psychiatric or non-psychiatric illnesses receiving antidepressant treatment should be informed to monitor the patient daily for agitation, irritability, or unusual behavioral changes, as well as suicidal tendencies, and to report such symptoms to healthcare professionals immediately. While a causal relationship has not been established between the presence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggression, impulsivity, akathisia, hypomania, and/or mania and the exacerbation of depression and/or suicidal impulses, there is concern that these symptoms may be precursors to suicidal ideation. Therefore, for patients whose depression continues to worsen, or who experience sudden suicidal ideation or symptoms that may indicate worsening depression or suicidal ideation, a change in treatment or discontinuation of treatment should be considered, especially if these symptoms are severe, sudden onset, or are not the primary symptoms present at the time of consultation. If the decision is made to discontinue treatment, the venlafaxine dose should be reduced as quickly as possible, while being aware of the risks of abrupt discontinuation. This article describes a case of venlafaxine-induced serotonin syndrome in a patient whose condition relapsed after taking amitriptyline, despite a two-week interval between discontinuing one medication and starting another. Electroencephalography (EEG) may play an important role in diagnosis. With the widespread use of selective serotonin reuptake inhibitors (SSRIs), increased awareness of serotonin syndrome is crucial. Furthermore, attention should be paid to drug interactions that may lead to this syndrome. For more complete data on venlafaxine (20 total), please visit the HSDB records page.

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Pharmacodynamics
Venlafaxine is an antidepressant that relieves symptoms of various mental illnesses by increasing the levels of neurotransmitters in synapses. Venlafaxine does not have muscarinic, histaminergic, or adrenergic effects.

C17H27NO2

277.40178

277.204

93413-69-5

Venlafaxine hydrochloride;99300-78-4;Venlafaxine-d6;1020720-02-8;Venlafaxine-d6-1;940297-06-3

5656

White to off-white solid powder

1.1±0.1 g/cm3

397.6±27.0 °C at 760 mmHg

72-74°C

194.2±23.7 °C

0.0±1.0 mmHg at 25°C

1.544

2.91

1

3

5

20

279

0

PNVNVHUZROJLTJ-UHFFFAOYSA-N

InChI=1S/C17H27NO2/c1-18(2)13-16(17(19)11-5-4-6-12-17)14-7-9-15(20-3)10-8-14/h7-10,16,19H,4-6,11-13H2,1-3H3

1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexan-1-ol

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.)