General
Preferred name
duloxetine
Synonyms
DULOXETINE HYDROCHLORIDE ()
(S)-Duloxetine hydrochloride ()
CPD000469136 ()
(S)-Duloxetine ()
LY248686 ()
LY-248686 hydrochloride ()
Duloxetine HCl ()
LY-248686 HCl ()
LY-248686 hydrochloride(S)-Duloxetine hydrochloride ()
Cymbalta ()
Duloxetine (hydrochloride) ()
LY-248686 ()
Duloxetine (as hydrochloride) ()
Yentreve ()
Duloxetine mylan ()
LY248686 HCL ()
LY-248686 HCL ()
Ariclaim ()
NSC-759112 ()
Drizalma sprinkle ()
Duciltia ()
Xeristar ()
(S)-Duloxetine (hydrochloride) ()
(S)-Duloxetine (hydrochloride) (CRM) ()
P&D ID
PD003013
CAS
116539-59-4
116539-58-3
136434-34-9
Tags
natural product
drug
available
Approved by
FDA
First approval
2004
Drug Status
approved
withdrawn
Drug indication
Depression
Antidepressant
Max Phase
Phase 4
Probe control
Probe control not defined
Orthogonal probes
0
No orthogonal probes found
Similar probes
0
No structurally similar probes found
Structure
P&D probe-likeness score
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
HALF-LIFE
Mean of 12 h with a range of 8-17.[label,A14807]
INDICATION
**Indicated** for:; ; 1) Management of Major Depressive Disorder.[label]; ; 2) Management of Generalized Anxiety Disorder.[label]; ; 3) Management of diabetic peripheral neuropathy.[label]; ; 4) Management of fibromyalgia.[label]; ; 5) Management of chronic musculoskeletal pain.[label]; ; 6) Management of osteoarthritis of the knee in adults.[L6364]; ; 7) Management of chronic lower back pain in adults.[L6364]; ; 8) Management of stress urinary incontinence in adult women.[L6367]; ; **Off-label** uses include:; ; 1) Management of chemotherapy-induced peripheral neuropathy.[A178603]; ; 2) Management of stress urinary incontinence in adult men after prostatectomy until recovery is complete.[L6370]
ROE
About 70% of duloxetine is excreted in the urine mainly as conjugated metabolites.[label] 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.[A14807]
ABSORPTION
Duloxetine is incompletely absorbed with a mean bioavailability of 50% although there is wide variability in the range of 30-80%.[A14807] 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.[label] 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.[A14807] These are attributed to delayed gastric emptying in both cases but are not expected to impact therapy to a clinically significant degree.
DESCRIPTION
Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) antidepressant.
(GtoPdb)
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.[A178663,A178666] 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.[A178669] 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.[A178666,A178705] 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.[A178711]; ; 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.[A178714]; ; Increased blood pressure is a common side effect with duloxetine due to vasoconstriction mediated by the intended increase in norepinephrine signaling.[label,T116]
TOXICITY
**Overdose**; ; Fatalities have been reported with doses of 1000mg involving both mixed drugs as well as duloxetine alone.[label] 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).[label] 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).[label]; ; **Lactation**; ; An estimated 25% of plasma duloxetine appears in breast milk with the estimated daily infant dose being 0.14% of the maternal dose.[label] Breast milk concentrations have been observed to peak 3 hours after administration.
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.
DESCRIPTION
Antibiotic; inhibits protein synthesis
(Tocris Bioactive Compound Library)
DESCRIPTION
Potent 5-HT and NA reuptake inhibitor; also blocks dopamine reuptake
(Tocriscreen Plus)
DESCRIPTION
Duloxetine is a serotonin-norepinephrine reuptake inhibitor (Ki=4.6 nM), used for major depressive disorder, generalized anxiety disorder, fibromyalgia and neuropathic pain.
(BOC Sciences Bioactive Compounds)
[[ p.pathway_name ]]
[[ compound.targets[tid].gene_name ]]
Cell lines
0
Organisms
1
Compound Sets
30
AdooQ Bioactive Compound Library
Bioprocess diversity set
BOC Sciences Bioactive Compounds
ChEMBL Approved Drugs
ChEMBL Drugs
Drug Repurposing Hub
DrugBank
DrugBank Approved Drugs
DrugCentral
DrugCentral Approved Drugs
DrugMAP
DrugMAP Approved Drugs
Enamine BioReference Compounds
EU-OPENSCREEN Bioactive Compound Library
Guide to Pharmacology
LSP-MoA library (Laboratory of Systems Pharmacology)
MedChem Express Bioactive Compound Library
Natural product-based probes and drugs
NCATS Inxight Approved Drugs
NIH Clinical Collections (NCC)
Novartis Chemogenetic Library (NIBR MoA Box)
NPC Screening Collection
Selleckchem Bioactive Compound Library
TargetMol Bioactive Compound Library
The Spectrum Collection
Tocris Bioactive Compound Library
Tocriscreen Plus
Withdrawn 2.0
[[ a.name ]]
[[ ligand_id ]]
free of charge
External IDs
68
Molecular Weight
297.12
Hydrogen Bond Acceptors
3
Hydrogen Bond Donors
1
Rotatable Bonds
6
Ring Count
3
Aromatic Ring Count
3
cLogP
4.63
TPSA
21.26
Fraction CSP3
0.22
Chiral centers
1.0
Largest ring
6.0
QED
0.72
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Target Type
Transporters
Target
Serotonin Transporter
Sert (Sodium-dependent)
DA transporter
Noradrenaline transporter (Sodium-dependent)
HTR2A, HTR2C, HTR6, SLC6A2, SLC6A3, SLC6A4
5-HT Receptor,Serotonin Transporter
Biological process
Mitosis & chromosome segregation
Pathway
Neuronal Signaling
GPCR/G protein
Neuroscience
Primary Target
5-HT Transporters
MOA
Inhibitor
Norepinephrine Transporter (NET) Inhibitors
Serotonin Transporter (SERT) Inhibitors
norepinephrine reuptake inhibitor, serotonin–norepinephrine reuptake inhibitor (SNRI)
Member status
member
Indication
depression, generalized anxiety disorder (GAD), muscle pain, peripheral neuropathy
ATC
N06AX21
Therapeutic Indication
Antidepressant
Therapeutic Class
CNS & PNS
Antidepressants
VGSC Target
Nav1.5
Solubility
Soluble in Methanol (Slightly), Water (Slightly, Heated)
Source data
