DULOXETINE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C18H19NOS
Molecular Weight	297.415
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CNCC[C@H](OC1=C2C=CC=CC2=CC=C1)C3=CC=CS3

InChI

InChIKey=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

HIDE SMILES / InChI

Molecular Formula	C18H19NOS
Molecular Weight	297.415
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

Duloxetine (brand names Cymbalta, Yentreve, and in parts of Europe, Xeristar or Ariclaim) is indicated for the acute and maintenance treatment of major depressive disorder (MDD), as well as acute management of generalized anxiety disorder. Also used for the management of neuropathic pain associated with diabetic peripheral neuropathy, and fibromyalgia. Has been used in the management of moderate to severe stress urinary incontinence (SUI) in women. It is manufactured and marketed by Eli Lilly and Company. Duloxetine has not yet been FDA approved for stress urinary incontinence or for fibromyalgia. Duloxetine is a selective SNRI (selective serotonin-norepinephrine reuptake inhibitor). Duloxetine is a systemic drug therapy which affects the body as a whole. Known also under the code name LY248686, it is a potent dual reuptake inhibitor of serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE), possessing comparable affinities in binding to NE- and 5-HT transporter sites. It is a less potent inhibitor of dopamine reuptake.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Serotonin transporter 178	Inhibitor 8,297	10.4 nM [IC50]
Norepinephrine transporter 191	Inhibitor 8,297	1.58 nM [IC50]
HERG 92	Inhibitor 8,297	142.8 µM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Major depressive disorder 173	Primary	Approved 8,429	Cymbalta
Generalized anxiety disorder 32	Primary	Approved 8,429	Cymbalta
Fibromyalgia 89	Palliative	Approved 8,429	Cymbalta

C_max

Value	Dose	Analyte	Population
10.44 μg/L	15 mg single, oral	DULOXETINE plasma	Homo sapiens
31.82 μg/L	30 mg single, oral	DULOXETINE plasma	Homo sapiens
55.88 μg/L	60 mg single, oral	DULOXETINE plasma	Homo sapiens
43.09 μg/L	30 mg 1 times / day multiple, oral	DULOXETINE plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
175.39 μg × h/L	15 mg single, oral	DULOXETINE plasma	Homo sapiens
489.35 μg × h/L	30 mg single, oral	DULOXETINE plasma	Homo sapiens
1073.99 μg × h/L	60 mg single, oral	DULOXETINE plasma	Homo sapiens
840.26 μg × h/L	30 mg 1 times / day multiple, oral	DULOXETINE plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
9.52 h	15 mg single, oral	DULOXETINE plasma	Homo sapiens
10.19 h	30 mg single, oral	DULOXETINE plasma	Homo sapiens
11.89 h	60 mg single, oral	DULOXETINE plasma	Homo sapiens
11.39 h	30 mg 1 times / day multiple, oral	DULOXETINE plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
10%			DULOXETINE plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
60 mg 2 times / day multiple, oral Recommended	unhealthy, 17 - 89	Disc. AE: Nausea...
60 mg 2 times / day multiple, oral Recommended	unhealthy, 17 - 89	Disc. AE: Nausea, Vomiting...
60 mg 2 times / day multiple, oral Recommended	unhealthy, 17 - 89	Disc. AE: Nausea, Dizziness...
60 mg 2 times / day multiple, oral Recommended	unhealthy, 17 - 89	Disc. AE: Nausea, Somnolence...
2820 mg single, oral Overdose	unhealthy, 25	Disc. AE: Generalized tonic-clonic seizure, Blurred vision...

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AEs

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AE	Significance	Dose	Population
Nausea	1.3% Disc. AE	60 mg 2 times / day multiple, oral Recommended	unhealthy, 17 - 89
Dizziness	1% Disc. AE	60 mg 2 times / day multiple, oral Recommended	unhealthy, 17 - 89
Vomiting	1.3% Disc. AE	60 mg 2 times / day multiple, oral Recommended	unhealthy, 17 - 89
Nausea	3.7% Disc. AE	60 mg 2 times / day multiple, oral Recommended	unhealthy, 17 - 89
Fatigue	1.1% Disc. AE	60 mg 2 times / day multiple, oral Recommended	unhealthy, 17 - 89

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 781	inhibitor 1,767 inducer 389	substrate 1,217 inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP3A 214 P-gp 1,461	CYP1A2 1,054 CYP2C11 8 BCRP 561	CYP1A2 701 CYP2C19 293 CYP2E1 128 CYP2A6 79

Drug as perpetrator

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Target	Modality	Activity	Clinical evidence
CYP2A6 739	inducer 1,573	likely
CYP2C19 1,553	inducer 1,573	likely
CYP2C9 1,819	inducer 1,573	likely
CYP2E1 970	inducer 1,573	likely
CYP2D6 1,891	inhibitor 3,277	moderate	yes (co-administration study)

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP2C11 8	substrate 3,367	likely
BCRP 561	substrate 3,367	no
CYP1A2 1,054	substrate 3,367	yes	yes (co-administration study)
CYP2D6 1,217	substrate 3,367	yes	yes (co-administration study)

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
AA Blocks	AA000CN4	https://www.aablocks.com/goods/Goods/detail?id=AA000CN4
abcr GmbH	AB457907	http://www.abcr.com/shop/en/AB457907
AEchem Scientific Corp., USA	AE1-015921	http://www.aechemsc.com/info_products/AE1-015921.php
Ambinter	Amb2383482	http://www.ambinter.com/reference/2383482
Angene	AGN-PC-0WH8CM	http://www.angenechemical.com/productshow/AGN-PC-0WH8CM.html

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PubMed

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Title	Date	PubMed
[Serotonin-noradrenaline reuptake inhibitors(SNRIs)].	2001 Aug	11519152
Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors.	2001 Dec	11750180
Can monoamine-based therapies be improved?	2002	15453009
Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial.	2002 Apr	12000204
Somatic symptoms, depression, and antidepressant treatment.	2002 Apr	12000203

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Patents

Sample Use Guides

In Vivo Use Guide

Dosage for Treatment of Major Depressive Disorder Administer CYMBALTA (Duloxetine) at a total dose of 40 mg/day (given as 20 mg twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily). For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily.

Route of Administration: Oral

In Vitro Use Guide

The 50% inhibitory concentration (IC50) of duloxetine for the resting and inactivated wild-type hNav1.7 Na+ channel were 22.1+/-0.4 and 1.79+/-0.10 uM, respectively. Inhibitory effects were even more pronounced when using a mammalian cell line resulting in a 34 or 59% current decrease by 10 or 30 uM duloxetine, respectively.

Substance Class	Chemical
Record UNII	O5TNM5N07U
Record Status	`Validated (UNII)`
Record Version

Show entries

Name

Type

Language

DULOXETINE

Official Name

English

YENTREVE

Brand Name

English

DULOXETINE [HSDB]

Common Name

English

LY-248686

Code

English

2-THIOPHENEPROPANAMINE, N-METHYL-.GAMMA.-(1-NAPHTHALENYLOXY)-, (S)-

Systematic Name

English

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Classification Tree

Code System

Code

Established Pharmacologic Class

NDF-RT

N0000175749

Other antidepressants

WHO-VATC

QN06AX21

Norepinephrine Transporter Interactions

NDF-RT

N0000000102

MENTAL DISORDERS

EMA ASSESSMENT REPORTS

XERISTAR (AUTHORIZED: ANXIETY DISORDERS)

Agent Affecting Nervous System

NCI_THESAURUS

C265

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Code System

Code

Type

Description

HSDB

7368

PRIMARY

IUPHAR

202

PRIMARY

DAILYMED

O5TNM5N07U

PRIMARY

FDA UNII

O5TNM5N07U

PRIMARY

WIKIPEDIA

DULOXETINE

PRIMARY

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Related Record

Type

Details


					VK4SQL11C0

CYTOCHROME P450 1A2

METABOLIC ENZYME -> SUBSTRATE

Comments:

CYP1A2 inhibition increases duloxetine exposure to a clinically significant degree.


					8E4LAA4357

CYTOCHROME P450 2D6

METABOLIC ENZYME -> INHIBITOR

Comments:

Cmax/IC50=0,2

Qualification:

IC50

Amount:

2.4 MICROMOLAR (average)


					6D53G0FD0Z

PLASMA PROTEIN FRACTION (HUMAN)

BINDER->LIGAND

Interaction Type:

BINDING

Amount:

[>90] % (average)


					HN86OLH1NW

SODIUM-DEPENDENT NORADRENALINE TRANSPORTER

TARGET -> INHIBITOR

Qualification:

IC50

Amount:

0.8 NANOMOLAR (average)


					O5TNM5N07U

DULOXETINE

EXCRETED UNCHANGED

Comments:

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.

Qualification:

URINE

Amount:

[<1] % (average)

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Related Record

Type

Details


					B18NZM26WW

5-HYDROXY-6-METHOXY DULOXETINE

METABOLITE INACTIVE -> PARENT


					6B3S58SVQ2

N-DESMETHYLDULOXETINE

METABOLITE -> PARENT

Comments:

Elimination half-life 11-16 hours. 72% oral excreted inurine and 15% in feces.

Qualification:

URINE


					59622HY2AF

5-HYDROXY DULOXETINE .BETA.-D-GLUCURONIDE

METABOLITE INACTIVE -> PARENT

Qualification:

URINE


					24CAA38X5F

5-HYDROXYDULOXETINE

METABOLITE INACTIVE -> PARENT

Interaction Type:

MAJOR


					24CAA38X5F

5-HYDROXYDULOXETINE

METABOLITE INACTIVE -> PARENT

Interaction Type:

MAJOR

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Related Record

Type

Details


					O5TNM5N07U

DULOXETINE

ACTIVE MOIETY

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Name	Property Type	Amount	Parameters
Tmax	PHARMACOKINETIC	[6 to 10] hours (average)	EFFECT OF FOOD: NONE

MAXIMUM TOLERATED DOSE	TOXICITY	PAIN	GENERALIZED ANXIETY DISORDER: 120 MG/DAY MAJOR DEPRESSIVE DISORDER: 120 MG/DAY

Volume of Distribution	PHARMACOKINETIC	23.4 Liters/Kilogram (average)

Biological Half-life	PHARMACOKINETIC	12 hours [8 to 17] (average)

CSF/PLASMA RATIO	PHARMACOKINETIC	MOL RATIO 0.023 [>0.2] (average)	SPECIES PHARMACOKINETIC HUMAN

Route of Elimination	PHARMACOKINETIC	MOLE PERCENT OF AMOUNT EXCRETED 70 % (average) RENAL, AS METABOLITES	EXCRETED UNCHANGED: LESS THAN 1%

Route of Elimination	PHARMACOKINETIC	MOLE PERCENT OF AMOUNT EXCRETED 20 % (average) FECAL

PROTEIN BINDING	PHARMACOKINETIC	[>90] % (average)

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator