hSERT ( IC50 = 47.3 nM ); hNET ( IC50 = 531.3 nM )

体外活性：去甲文拉法辛是一种血清素-去甲肾上腺素再摄取抑制剂，是抗抑郁药文拉法辛的活性代谢物。与文拉法辛类似，去甲文拉法辛抑制神经元对血清素和去甲肾上腺素的摄取。去甲文拉法辛对人多巴胺 (DA) 转运蛋白显示出弱结合亲和力（100 μM 时抑制 62%）。 Desvenlafaxine 抑制 hSERT 或 hNET 的 [3H]5-HT 或 [3H]NE 摄取，IC50 分别为 47.3 和 531.3 nM。去甲文拉法辛具有抑制 CYP2D6 的潜力，这可能导致通过该途径代谢的药物浓度增加。去甲文拉法辛也可能诱导 CYP3A4，这可能会影响通过该酶代谢的药物的代谢。

去甲文拉法辛迅速渗透雄性大鼠大脑和下丘脑。与雄性大鼠下丘脑的基线相比，去甲文拉法辛显着增加细胞外 NE 水平，但使用微透析对 DA 水平没有影响。去甲文拉法辛在 100 至 600 mg/天的剂量范围内表现出线性且与剂量成比例的药代动力学单剂量曲线。口服制剂的绝对生物利用度为80.5%。

Absorption, Distribution and Excretion
The absolute oral bioavailability of desvenlafaxine after oral administration is about 80%. The time to reach maximal concentration (Tmax) is estimated to be 7.5 hours after oral administration. The AUC in a 24 h dosing interval at steady state with a 100 mg dose was also calculated to be 6747 ng*h/mL, and the Cmax 376 ng/mL. Ingestion of a high-fat meal (800 to 1000 calories) increased desvenlafaxine Cmax about 16% and had no effect on AUC.
Desvenlafaxine is mainly excreted in the urine. Approximately 45% of desvenlafaxine is excreted unchanged in urine at 72 hours after oral administration. Approximately 19% of the administered dose is excreted as the glucuronide metabolite and <5% as the oxidative metabolite (N,O-didesmethyl venlafaxine) in urine.
The steady-state volume of distribution of desvenlafaxine is 3.4 L/kg.
Following the administration of 100 mg of desvenlafaxine in healthy subjects from 18 to 45 years of age, the renal clearance was calculated to be 222 ± 82 mL/min.
The plasma protein binding of desvenlafaxine is low (30%) and is independent of drug concentration. The desvenlafaxine volume of distribution at steady-state following intravenous administration is 3.4 L/kg, indicating distribution into nonvascular compartments.
The absolute oral bioavailability of Pristiq after oral administration is about 80%. Mean time to peak plasma concentrations (Tmax) is about 7.5 hours after oral administration.
Approximately 45% of desvenlafaxine is excreted unchanged in urine at 72 hours after oral administration. Approximately 19% of the administered dose is excreted as the glucuronide metabolite and < 5% as the oxidative metabolite (N,O-didesmethylvenlafaxine) in urine
Desvenlafaxine is excreted into human milk.
For more Absorption, Distribution and Excretion (Complete) data for Desvenlafaxine (6 total), please visit the HSDB record page.

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Metabolism / Metabolites
Desvenlafaxine is primarily metabolized by conjugation (mediated by UGT isoforms) and, to a minor extent, through oxidative metabolism. O-glucuronide conjugation is likely be catalyzed by UGT1A1, UGT1A3, UGT2B4, UGT2B15, and UGT2B17. CYP3A4 and potentially CYP2C19 mediates the oxidative metabolism (N-demethylation) of desvenlafaxine to N,O-didesmethyl venlafaxine. The CYP2D6 metabolic pathway is not involved. The pharmacokinetics of desvenlafaxine was similar in subjects with CYP2D6 poor and extensive metabolizer phenotype.
Desvenlafaxine is primarily metabolized by conjugation (mediated by UGT isoforms) and, to a minor extent, through oxidative metabolism. CYP3A4 is the cytochrome P450 isozyme mediating the oxidative metabolism (N-demethylation) of desvenlafaxine. The CYP2D6 metabolic pathway is not involved, and after administration of 100 mg, the pharmacokinetics of desvenlafaxine was similar in subjects with CYP2D6 poor and extensive metabolizer phenotype. ... Approximately 19% of the administered dose is excreted as the glucuronide metabolite and < 5% as the oxidative metabolite (N,O-didesmethylvenlafaxine) in urine

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Biological Half-Life
The mean terminal half-life is 11.1 hours and may be prolonged in patients with renal and/or moderate to severe hepatic impairment.
The mean half life changed from approximately 10 hours in healthy subjects and subjects with mild hepatic impairment to 13 and 14 hours in moderate and severe hepatic impairment, respectively.
The mean terminal half-life, is approximately 11 hours.

Interactions
Desvenlafaxine does not inhibit or induce the CYP3A4 isoenzyme in vitro. Concurrent administration of desvenlafaxine (400 mg daily; 8 times the recommended dosage) and midazolam (single 4-mg dose), a CYP3A4 substrate, decreased the AUC and peak plasma concentrations of midazolam by approximately 31 and 16%, respectively. The manufacturer states that concurrent use of desvenlafaxine with a drug metabolized by CYP3A4 can result in lower exposures to that drug.
Selective serotonin-reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitor (SNRIs), including desvenlafaxine, may increase the risk of bleeding events. Concurrent administration of aspirin, nonsteroidal anti-inflammatory agents, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiologic studies have demonstrated an association between the use of drugs that interfere with serotonin reuptake and the occurrence of GI bleeding. Bleeding events related to SSRI and SNRI use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. The manufacturer recommends that patients be advised of the risk of bleeding associated with the concomitant use of desvenlafaxine and aspirin or other nonsteroidal anti-inflammatory agents, warfarin, or other drugs that affect coagulation or bleeding.
Desvenlafaxine minimally inhibits the cytochrome P-450 (CYP) 2D6 isoenzyme. In a study in healthy adults, concurrent administration of desvenlafaxine (100 mg daily) and desipramine (single 50-mg dose), a CYP2D6 substrate, increased peak plasma concentrations and AUCs of desipramine by approximately 25 and 17%, respectively. The manufacturer states that concomitant use of desvenlafaxine with a drug metabolized by CYP2D6 can result in higher plasma concentrations of that drug.
In a clinical study, desvenlafaxine did not increase impairment of mental and motor skills caused by alcohol. However, the manufacturer recommends avoiding concomitant alcohol consumption during desvenlafaxine therapy.
For more Interactions (Complete) data for Desvenlafaxine (11 total), please visit the HSDB record page.

[1]. Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor. J Pharmacol Exp Ther, 2006. 318(2): p. 657-65.

[2]. Sopko, M.A., Jr., M.J. Ehret, and M. Grgas, Desvenlafaxine: another "me too" drug? Ann Pharmacother, 2008. 42(10): p. 1439-46.

O-desmethylvenlafaxine is a tertiary amino compound that is N,N-dimethylethanamine substituted at position 1 by a 1-hydroxycyclohexyl and 4-hydroxyphenyl group. It is a metabolite of the drug venlafaxine. It has a role as a marine xenobiotic metabolite, a drug metabolite and an antidepressant. It is a member of cyclohexanols, a member of phenols and a tertiary amino compound.
Desvenlafaxine (O-desmethylvenlafaxine) is the 0-demetyhlated active metabolite of [venlafaxine]. Like its parent drug, desvenlafaxine is also an antidepressant belonging to the class of serotonin-norepinephrine reuptake inhibitor (SNRI) class. It was approved by the FDA in 2008 for the treatment of adults with major depressive disorder (MDD). MDD is a highly prevalent psychiatric disorder, with a lifetime prevalence estimate of 16% in the US alone and 12.8% in Europe. Although the exact mechanism of pathophysiology is still unknown, imbalances or deficiencies of monoamines have been heavily implicated, thus the rationale behind the use of SNRI to treat MDD. Desvenlafaxine has a very similar pharmacological, efficacy, and safety profile as [venlafaxine]. The major difference is the potential for drug interaction since venlafaxine is mainly metabolized by CYP2D6 while desvenlafaxine is conjugated by UGT; therefore, desvenlafaxine is less likely to cause drug-drug interaction when taken with medications affecting the CYP2D6 pathway.
Desvenlafaxine is a Serotonin and Norepinephrine Reuptake Inhibitor. The mechanism of action of desvenlafaxine is as a Norepinephrine Uptake Inhibitor, and Serotonin Uptake Inhibitor, and Cytochrome P450 2D6 Inhibitor.
Desvenlafaxine is a synthetic phenethylamine bicyclic derivative with antidepressant activity. Desvenlafaxine is a selective reuptake inhibitor of serotonin and norepinephrine due to its high binding affinities to the pre-synaptic serotonin and norepinephrine transporters. By blocking both transporters, this agent prolongs neurotransmitter activities of both serotonin and norepinephrine, thereby alleviating depressive state.
A cyclohexanol and phenol derivative and metabolite of venlafaxine that functions as a SEROTONIN AND NORADRENALINE REUPTAKE INHIBITOR (SNRI) and is used as an ANTIDEPRESSIVE AGENT.
See also: Desvenlafaxine Succinate (has salt form); Toludesvenlafaxine (is active moiety of); Desvenlafaxine Fumarate (is active moiety of) ... View More ...

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Drug Indication
Desvenlafaxine is indicated for the treatment of major depressive disorder in adults. It has also been used off-label to treat hot flashes in menopausal women.
FDA Label

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Mechanism of Action
The exact mechanism of the antidepressant action of desvenlafaxine is unknown but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake. Particularly, desvenlafaxine has been found to inhibit the serotonin, norepinephrine, and dopamine transporters with varying degrees of affinity. Desvenlafaxine inhibits serotonin transporters with 10 times the affinity of norepinephrine transporters, and dopamine transporters with the lowest affinity.
The exact mechanism of antidepressant action of desvenlafaxine has not been fully elucidated but appears to be associated with the drug's potentiation of serotonergic and noradrenergic activity in the CNS. Like venlafaxine and duloxetine, desvenlafaxine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake; however, inhibition of dopamine reuptake at concentrations that inhibit serotonin and norepinephrine reuptake appears unlikely in most patients. The drug does not inhibit monoamine oxidase (MAO) and has not demonstrated significant affinity for muscarinic cholinergic, H1-histaminergic, alpha1-adrenergic, dopaminergic, gamma-aminobutyric acid (GABA), glutamate, and opiate receptors in vitro.

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Therapeutic Uses
Antidepressive Agents; Neurotransmitter Uptake Inhibitors
Used to treat major depressive, generalized anxiety, social anxiety and panic disorders /Desvenlafaxine succinate monohydrate/
Like some other selective serotonin and norepinephrine reuptake inhibitors (SNRIs) and selective serotonin-reuptake inhibitors (SSRIs), desvenlafaxine succinate has been studied for the management of vasomotor symptoms in postmenopausal women. /NOT included in US product labeling/
Desvenlafaxine succinate is used in the treatment of major depressive disorder in adults. /Included in US product labeling/
Recent reviews have questioned whether the serotonin-norepinephrine reuptake inhibitor (SNRI) desvenlafaxine succinate offers any practical clinical advantages over existing SNRIs. The following case is one instance where it appears that this SNRI offers unique safety and benefit. Presented is a case report of a patient with Gilbert's syndrome, longstanding social phobia, and more recent depressive disorder not otherwise specified, who was found to have elevated liver transaminases when prescribed both duloxetine and venlafaxine. The patient subsequently responded to desvenlafaxine but without liver abnormalities. In this patient with Gilbert's Syndrome, desvenlafaxine's lack of metabolism through the cytochrome P450 (CYP) 2D6 pathway may explain the avoidance of these abnormalities and thus suggests a possible therapeutic role for this SNRI in similarly susceptible patients.

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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. Pristiq is not approved for use in pediatric patients.
In patients with moderate or severe renal impairment or end-stage renal disease (ESRD) the clearance of Pristiq was decreased, thus prolonging the elimination half-life of the drug. As a result, there were potentially clinically significant increases in exposures to Pristiq. Dosage adjustment (50 mg every other day) is necessary in patients with severe renal impairment or ESRD. The doses should not be escalated in patients with moderate or severe renal impairment or ESRD.
Sustained increases in blood pressure have been reported. In controlled studies, sustained hypertension occurred in 0.7-2.3% of patients receiving desvenlafaxine dosages from 50-400 mg daily, with a suggestion of a higher incidence (2.3%) in those receiving 400 mg of the drug daily. In addition, some cases of elevated blood pressure requiring immediate treatment have been reported with desvenlafaxine. Sustained blood pressure increases could have adverse consequences in patients receiving the drug. Therefore, the manufacturer recommends that preexisting hypertension be controlled before initiating desvenlafaxine therapy and that regular blood pressure monitoring be performed in patients receiving the drug. Desvenlafaxine should be used cautiously in patients with preexisting hypertension or other underlying conditions that may be compromised by increases in blood pressure. Dosage reduction or drug discontinuance should be considered in patients who experience a sustained increase in blood pressure during therapy.
Treatment with selective serotonin-reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitor (SNRIs), including desvenlafaxine, may result in hyponatremia.In many cases, hyponatremia appears to be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium concentrations lower than 110 mmol/L have been reported. Geriatric individuals and patients receiving diuretics or who are otherwise volume depleted may be at greater risk of developing hyponatremia. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls; more severe and/or acute cases have been associated with hallucinations, syncope, seizures, coma, respiratory arrest, and death. Initiate appropriate medical intervention and consider drug discontinuance in patients with symptomatic hyponatremia.
For more Drug Warnings (Complete) data for Desvenlafaxine (20 total), please visit the HSDB record page.

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Pharmacodynamics
Desvenlafaxine is a selective serotonin and norepinephrine reuptake inhibitor. It lacks significant activity on muscarinic-cholinergic, H₁-histaminergic, or α₁-adrenergic receptors in vitro, or inhibitory activity against monoamine oxidase. Desvenlafaxine does not appear to exert activity against calcium, chloride, potassium and sodium ion channels and also lacks monoamine oxidase (MAO) inhibitory activity. It was also shown to lack significant activity against the cardiac potassium channel, hERG, in vitro. Electrocardiograms were obtained from 1,492 desvenlafaxine treated patients with major depressive disorder and 984 placebo-treated patients in clinical studies lasting up to 8 weeks. No clinically relevant differences were observed between desvenlafaxine treated and placebo-treated patients for QT, QTc, PR, and QRS intervals. In a thorough QTc study with prospectively determined criteria, desvenlafaxine did not cause QT prolongation. No difference was observed between placebo and desvenlafaxine treatments for the QRS interval.

C16H25NO2

263.38

263.188

C, 72.96; H, 9.57; N, 5.32; O, 12.15

93413-62-8

Desvenlafaxine succinate hydrate; 386750-22-7; (S)-(+)-O-Desmethyl Venlafaxine-d6; 1062609-99-7; Desvenlafaxine succinate; 448904-47-0; Desvenlafaxine fumarate; 93414-04-1; Desvenlafaxine hydrochloride; 300827-87-6; (S)-(+)-O-Desmethyl Venlafaxine; 142761-12-4; (R)-(-)-O-Desmethyl Venlafaxine-d6; 1062609-96-4; 1147940-37-1 (benzoate)

125017

White to off-white solid powder

1.1±0.1 g/cm3

403.8±25.0 °C at 760 mmHg

208-213ºC

193.2±21.8 °C

0.0±1.0 mmHg at 25°C

1.573

2.26

43.7

2

3

4

19

266

0

OC1C=CC(C(C2(CCCCC2)O)CN(C)C)=CC=1

KYYIDSXMWOZKMP-UHFFFAOYSA-N

InChI=1S/C16H25NO2/c1-17(2)12-15(13-6-8-14(18)9-7-13)16(19)10-4-3-5-11-16/h6-9,15,18-19H,3-5,10-12H2,1-2H3

4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (9.49 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (9.49 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (9.49 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液添加到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 0.5% methylcellulose+0.2% Tween 80 : 30 mg/mL

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。