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Duloxetine | CAS No: 116539-59-4 | GMP-certified suppliers
A medication that manages depression, anxiety, diabetic neuropathy, fibromyalgia, chronic musculoskeletal pain, osteoarthritis, lower back pain, and stress urinary incontinence in adults.
Therapeutic categories
Primary indications
- Indicated** for:
- Management of Major Depressive Disorder
- Management of Generalized Anxiety Disorder
Product Snapshot
- Duloxetine is an oral small molecule available in various capsule and tablet formulations, including delayed release and extended release forms, with additional topical cream options
- It is primarily used for the management of major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathy, fibromyalgia, chronic musculoskeletal pain, osteoarthritis of the knee, chronic lower back pain, and stress urinary incontinence in adult women
- Duloxetine is approved for use in key regulatory markets including the FDA (US), EMA (EU), and Health Canada
Clinical Overview
Pharmacologically, duloxetine increases synaptic concentrations of serotonin and norepinephrine by inhibiting their neuronal reuptake with less pronounced effect on dopamine reuptake. This action modulates neurotransmission in various central nervous system pathways implicated in mood regulation, pain perception, and urinary continence. In the spinal cord dorsal horn, duloxetine enhances descending inhibition of nociceptive signaling by activating serotonergic and adrenergic receptors on inhibitory interneurons, thereby raising the threshold for pain signal transmission. Its effect on stress urinary incontinence is mediated by increased serotonin and norepinephrine availability in Onuf’s nucleus, which enhances activation of motor neurons innervating the external urethral sphincter through 5-HT2, 5-HT3, and α1-adrenergic receptors.
Duloxetine undergoes hepatic metabolism primarily via cytochrome P450 enzymes CYP1A2 and CYP2D6 and exhibits moderate plasma protein binding. Its elimination half-life averages 12 hours, and clearance is largely renal, necessitating consideration in patients with hepatic or renal impairment.
Common adverse effects include increased blood pressure related to norepinephrine-mediated vasoconstriction. Other safety considerations involve potential serotonergic toxicity, including risk of serotonin syndrome, and interactions with other cytochrome P450 substrates and inhibitors. Attention to contraindications, dosing adjustments, and monitoring is essential in clinical use.
From an API sourcing and quality perspective, suppliers should ensure compliance with international pharmaceutical standards including stringent control of impurity profiles, reproducibility of physicochemical properties, and batch-to-batch consistency. Due to its metabolism via multiple CYP enzymes, impurity profiles must be characterized carefully to avoid any structural analogs with toxicological concerns. Confirming the absence of residual solvents and ensuring stable crystalline form are important parameters for manufacturing consistency and regulatory compliance.
Identification & chemistry
| Generic name | Duloxetine |
|---|---|
| Molecule type | Small molecule |
| CAS | 116539-59-4 |
| UNII | O5TNM5N07U |
| DrugBank ID | DB00476 |
Pharmacology
| Summary | Duloxetine is a serotonin-norepinephrine reuptake inhibitor with additional dopamine reuptake inhibition, enhancing synaptic concentrations of these neurotransmitters. Its pharmacodynamic effects include augmentation of descending inhibitory pain pathways in the spinal cord via serotonergic and adrenergic receptor activation, as well as enhanced activation of motor neurons innervating the external urinary sphincter through increased serotonin and norepinephrine signaling in Onuf’s nucleus. These actions underlie its therapeutic applications in mood disorders, neuropathic and musculoskeletal pain, and stress urinary incontinence. |
|---|---|
| Mechanism of action | 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. Action on the external urinary sphincter is mediated via duloxetine's CNS effects. Increased serotonin and norepinephrine concentrations in Onuf's nucleus leads to increased activation of 5-HT<sub>2</sub>, 5-HT<sub>3</sub>, and α<sub>1</sub> adrenergic receptors. 5-HT<sub>2</sub> and α<sub>1</sub> are both G<sub>q</sub> coupled and their activation increases the activity of the inositol trisphosphate/phospholipase C (IP<sub>3</sub>/PLC) pathway. This pathway leads to release of intracellular calcium stores, increasing intracellular calcium concentrations, and facilitating neuronal excitability. 5-HT<sub>3</sub> functions as a ligand-gated sodium channel which allows sodium to flow into the neuron when activated. Increased flow of sodium into the neuron contributes to depolarization and activation of voltage gated channels involved in action potential generation. The combined action of these three receptors contributes to increased excitability of the pudendal motor nerve in response to glutamate. Also related to duloxetine's action at the spinal cord is its modulation of pain. Increasing the concentration of serotonin and norepinephrine in the dorsal horn of the spinal cord increases descending inhibition of pain through activation of 5-HT<sub>1A</sub>, 5-HT<sub>1B</sub>, 5-HT<sub>1D</sub>, 5-HT<sub>2</sub>, 5-HT<sub>3</sub>, α<sub>1</sub>-adrenergic, and α<sub>2</sub>-adrenergic receptors. 5-HT<sub>2</sub>, 5-HT<sub>3</sub>, and α<sub>1</sub>-adrenergic mediate neuronal activation as described above. The activated neuron in this case is the GABAergic inhibitory interneuron which synapses onto the nociceptive projection neuron to inhibit the transmission of painful stimuli to the brain. The 5-HT<sub>1</sub> and α<sub>2</sub> receptors are G<sub>i</sub>/G<sub>o</sub> coupled and their activation leads to increased potassium current through inward rectifier channels and decreased adenylyl cyclase/protein kinase A signaling which contributes to neuronal inhibition. These inhibitory receptors are present on the projection neuron itself as well as the dorsal root ganglion which precedes it and serves to directly suppress the transmission of painful stimuli. The mechanisms involved in duloxetine's benefits in depression and anxiety have not been fully elucidated. Dysfunctional serotonin and norepinephrine signaling are thought to be involved and increases in the availability of these neurotransmitters at the synaptic cleft thought to mediate a therapeutic effect. It is postulated that the involvement of serotonin and norepinephrine in area responsible for emotional modulation such as the limbic system contributes to the effects in mood disorders specifically but this has yet to be confirmed. Duloxetine's hypertensive effect is related to its intended pharmacological effect. Increased availability of norepinephrine leads to activation of adrenergic receptors on the vascular endothelium. Since the action of α<sub>1</sub> receptors predominates, vasoconstriction results as the G<sub>q</sub> coupled receptor mediates calcium release from the sarcoplasmic reticulum to facilitate smooth muscle contraction. |
| 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.[label,T116] |
Targets
| Target | Organism | Actions |
|---|---|---|
| Sodium-dependent serotonin transporter | Humans | inhibitor |
| Sodium-dependent noradrenaline transporter | Humans | inhibitor |
| Sodium-dependent dopamine transporter | Humans | inhibitor |
ADME / PK
| Absorption | 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<sup>-1</sup>.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. |
|---|---|
| Half-life | Mean of 12 h with a range of 8-17.[label,A14807] |
| Protein binding | Over 90% bound to plasma proteins, primarily albumin and α1 acid-glycoprotein.[label,A14807] |
| Metabolism | Duloxetine is extensively metabolized primarily by CYP1A2 and CYP2D6 with the former being the greater contributor.[label,A14807] 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. |
| Route of elimination | 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.[label,A14807] Biliary secretion is thought to play a role due to timeline of fecal excretion exceeding the time expected of normal GI transit. |
| Volume of distribution | Apparent Vd of 1620-1800 L.[label,A14807] Duloxetine crosses the blood-brain barrier and collects in the cerebral cortex at a higher concentration than the plasma. |
| Clearance | 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. |
Formulation & handling
- Duloxetine is a small molecule with poor water solubility, formulated primarily for oral administration as capsules or delayed-release tablets.
- Avoid sprinkling capsule contents on food or liquids; the formulation is designed for intact oral ingestion.
- Alcohol should be avoided due to increased risk of liver toxicity; no significant food interaction affecting absorption is noted.
Regulatory status
| Lifecycle | The API is marketed in Canada, the EU, and the US, with primary patent protections in North America expiring between 2013 and 2020, while a key US patent extends protection until 2037, indicating a mature market with ongoing exclusivity in the US. |
|---|
| Markets | Canada, EU, US |
|---|
Supply Chain
| Supply chain summary | Duloxetine is originally manufactured by a single originator company, with branded products available across major markets including the US, EU, and Canada. Multiple packaging and distribution entities support its supply chain. Patent protection extending to 2037 in the US indicates limited current generic competition, with generics unlikely to enter the market in the near term. |
|---|
Safety
| Toxicity | **Overdose** Fatalities have been reported with doses of 1000mg involving both mixed drugs as well as duloxetine alone. Signs and symptoms of overdose include: somnolence, coma, serotonin syndrome, seizure, syncope, hypo- or hypertension, tachycardia, and vomiting. No antidote exists and the drug is unlikely to be cleared by hemodialysis. Supportive care is recommended along with activated charcoal and gastric lavage to reduce absorption. If serotonin syndrome occurs specific treatment such as temperature control or cyproheptadine may be initiated. **Carcinogenicity & Mutagenicity** Increased incidence of hepatocellular carcinomas and adenomas were reported in female mice fed 140 mg/kg/day duloxetine for 2 years, equivalent to 6 times the maximum recommended human dose (MRHD). No effect was reported with doses of 50mg/kg/day (2 time MRHD) in females or 100 mg/kg/day in males (4 times MRHD). Similar investigation in rats produced no carcinogenicity at doses of 27 mg/kg/day (2 times MRHD)in females and 36 mg/kg/day in males (4 times MRHD). No mutagenicity, clastogenicity, induction of sister chromatid exchange, or genotoxicity has been observed in toxicology investigations. **Reproductive Toxicity** Neither male or female rats displayed adverse reproductive effects at doses up to 45 mg/kg/day (4 times MRHD). **Lactation** An estimated 25% of plasma duloxetine appears in breast milk with the estimated daily infant dose being 0.14% of the maternal dose. Breast milk concentrations have been observed to peak 3 hours after administration. |
|---|
- Overdose may result in severe CNS and cardiovascular effects, including coma, seizure, serotonin syndrome, hypo- or hypertension, and tachycardia
- No specific antidote is available
- Carcinogenicity observed in female mice at exposures ≥6 times the maximum human dose
Duloxetine is a type of Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)
Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) belong to a vital subcategory of pharmaceutical active pharmaceutical ingredients (APIs) that have gained significant popularity in the treatment of various medical conditions. SNRIs work by modulating the levels of two essential neurotransmitters in the brain, namely serotonin and norepinephrine.
These APIs are commonly prescribed for managing a range of mental health disorders, including depression, anxiety disorders, and certain chronic pain conditions. By inhibiting the reuptake of serotonin and norepinephrine, SNRIs enhance their availability in the brain, leading to improved mood, increased energy levels, and reduced pain perception.
SNRIs exhibit a unique dual mechanism of action, making them distinct from other classes of antidepressant medications. By targeting both serotonin and norepinephrine reuptake, SNRIs provide a broader spectrum of therapeutic effects, making them effective in treating patients who do not respond well to other medications.
Due to their widespread usage and effectiveness, SNRIs have become a preferred choice for healthcare professionals. Some commonly prescribed SNRIs include duloxetine, venlafaxine, and desvenlafaxine. These APIs are typically available in oral formulations and are well-tolerated by most patients, with a favorable side effect profile.
In summary, SNRIs represent a significant subcategory of pharmaceutical APIs that play a crucial role in the management of mental health disorders and chronic pain conditions. Their unique dual mechanism of action and effectiveness make them a valuable treatment option for healthcare providers, ensuring improved patient outcomes and quality of life.
Duloxetine (Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)), classified under Antidepressants
Antidepressants are a category of pharmaceutical Active Pharmaceutical Ingredients (APIs) widely used in the treatment of depression and other mood disorders. These medications work by balancing the levels of certain chemicals in the brain called neurotransmitters, such as serotonin, norepinephrine, and dopamine.
There are several types of antidepressants available, each with its own mechanism of action and efficacy. Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed as a first-line treatment for depression. They prevent the reabsorption of serotonin, resulting in increased serotonin levels in the brain. Examples of popular SSRIs include fluoxetine, sertraline, and escitalopram.
Tricyclic antidepressants (TCAs) are another class of antidepressants that work by blocking the reuptake of both serotonin and norepinephrine. They are generally used when SSRIs are ineffective or not well-tolerated. Amitriptyline, nortriptyline, and imipramine are commonly prescribed TCAs.
Other antidepressants include serotonin-norepinephrine reuptake inhibitors (SNRIs), atypical antidepressants, and monoamine oxidase inhibitors (MAOIs). SNRIs, such as venlafaxine and duloxetine, inhibit the reuptake of both serotonin and norepinephrine. Atypical antidepressants, including bupropion and mirtazapine, have diverse mechanisms of action, targeting multiple neurotransmitters. MAOIs, such as phenelzine and tranylcypromine, work by inhibiting the enzyme monoamine oxidase, which breaks down neurotransmitters.
It is important to note that antidepressants may have various side effects and require close monitoring by healthcare professionals. Dosages and treatment duration vary based on individual needs and response. Antidepressants are typically prescribed as part of a comprehensive treatment plan that may include psychotherapy and lifestyle modifications.
In conclusion, antidepressants are a vital category of pharmaceutical APIs used to manage depression and related mood disorders. They act on neurotransmitters in the brain to alleviate symptoms and improve overall well-being. It is crucial to consult with a healthcare provider to determine the most suitable antidepressant and monitor its effects.
Duloxetine API manufacturers & distributors
Compare qualified Duloxetine API suppliers worldwide. We currently have 26 companies offering Duloxetine API, with manufacturing taking place in 9 different countries. Use the table below to review supplier type, countries of origin, certifications, product portfolio and GMP audit availability.
| Supplier | Type | Country | Product origin | Certifications | Portfolio |
|---|---|---|---|---|---|
| Alkem Labs. | Producer | India | India | CoA, USDMF, WC | 22 products |
| Dr. Sahu's Laboratories | Producer | India | India | BSE/TSE, CEP, CoA, FDA, GMP, MSDS | 70 products |
| Eli Lilly And Company | Producer | United States | United States | CoA, JDMF | 5 products |
| Erregierre | Producer | Italy | Italy | CoA, USDMF | 44 products |
| Global Pharma Tek | Distributor | India | India | BSE/TSE, CoA, FDA, GMP, ISO9001, MSDS | 484 products |
| HEC Pharm | Producer | Germany | Unknown | CoA, USDMF | 31 products |
| Hetero Drugs | Producer | India | Unknown | CEP, CoA, FDA, GMP, JDMF, KDMF, USDMF, WC | 98 products |
| Huadong Medicine | Producer | China | China | CEP, CoA, GMP | 4 products |
| Kolon Life Science | Producer | South Korea | South Korea | CoA | 32 products |
| KRKA | Producer | Slovenia | Unknown | CEP, CoA, GMP | 81 products |
| Lupin | Producer | India | India | CEP, CoA, FDA, GMP, USDMF, WC | 155 products |
| Menovo | Producer | China | China | CEP, CoA, EDMF/ASMF, FDA, GMP | 27 products |
| Moehs | Producer | Spain | Spain | CEP, CoA, EDMF/ASMF, GMP, Other, KDMF, USDMF | 50 products |
| MSN Labs. | Producer | India | India | CEP, CoA, FDA, GMP, JDMF, KDMF, USDMF, WC | 119 products |
| Mylan | Producer | India | India | CEP, CoA, FDA, GMP, KDMF, USDMF, WC | 201 products |
| SETV Global | Producer | India | India | CoA, FDA, GMP | 515 products |
| Signa | Producer | Mexico | Mexico | CoA, USDMF | 42 products |
| Sinoway industrial Co.,Lt... | Distributor | China | China | CoA, ISO9001, MSDS | 762 products |
| Sun Pharma | Producer | India | India | CoA, GMP, USDMF, WC | 219 products |
| Tenatra Exports Private L... | Distributor | India | India | BSE/TSE, CoA, FDA, GMP, MSDS | 263 products |
| Torrent Pharma | Producer | India | India | CoA, USDMF | 34 products |
| Veeprho Group | Producer | Czech Republic | Czech Republic | CoA | 140 products |
| Zhejiang Huayi | Producer | China | China | CEP, CoA, FDA | 9 products |
| Zhejiang Liaoyuan | Producer | China | China | CEP, CoA, FDA, GMP, USDMF | 5 products |
| Zhejiang Tiantai | Producer | China | China | CoA, WC | 7 products |
| Zhejiang Yongtai Pharma | Producer | China | China | CEP, CoA, USDMF | 5 products |
When sending a request, specify which Duloxetine API quality you need: for example EP (Ph. Eur.), USP, JP, BP, or another pharmacopoeial standard, as well as the required grade (base, salt, micronised, specific purity, etc.).
Use the list above to find high-quality Duloxetine API suppliers. For example, you can select GMP, FDA or ISO certified suppliers. Visit our help page to learn more about sourcing APIs via Pharmaoffer.
