AMITRIPTYLINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C20H23N
Molecular Weight	277.4033
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CN(C)CCC=C1C2=C(CCC3=C1C=CC=C3)C=CC=C2

InChI

InChIKey=KRMDCWKBEZIMAB-UHFFFAOYSA-N

InChI=1S/C20H23N/c1-21(2)15-7-12-20-18-10-5-3-8-16(18)13-14-17-9-4-6-11-19(17)20/h3-6,8-12H,7,13-15H2,1-2H3

HIDE SMILES / InChI

Molecular Formula	C20H23N
Molecular Weight	277.4033
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description

Amitriptyline is a derivative of dibenzocycloheptadiene and a tricyclic antidepressant (TCA) and is mainly used to treat symptoms of depression. It works on the central nervous system (CNS) by inhibiting the membrane pump mechanism responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons. Amitriptyline has been frequently used as an active comparator in clinical trials on newer antidepressants. It is rarely used as a first-line antidepressant nowadays due to its high degree of toxicity in overdose and generally poorer tolerability than the newer antidepressants.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Sodium-dependent noradrenaline transporter 38	Inhibitor 8,297	3.45 nM [IC50]
Sodium-dependent serotonin transporter 40	Inhibitor 8,297	13.3 nM [IC50]
5-hydroxytryptamine receptor 2A 69	Antagonist 2,778

Conditions

Condition	Modality	Targets	Highest Phase	Product
Depressive disorder 4	Preventing		Approved 8,429	AMITRIPTYLINE HYDROCHLORIDE

C_max

Value	Dose	Co-administered	Analyte	Population
15.3 ng/mL	75 mg single, oral		AMITRIPTYLINE plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
593 ng × h/mL	75 mg single, oral		AMITRIPTYLINE plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
20.4 h	75 mg single, oral		AMITRIPTYLINE plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
7.7%	150 mg 1 times / day multiple, oral		AMITRIPTYLINE plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
100 mg 1 times / day single, intravenous Studied dose	healthy, 21 to 70 years n = 5	Disc. AE: Bradycardia... Other AEs: Agitation, Dry mouth...
10 % 1 times / day single, topical Highest studied dose	unhealthy, 57 years n = 1	Other AEs: Thought disorder, Mental concentration difficult...
520.3 mg 1 times / day single, oral (mean) Studied dose	healthy, mean age 22.1 years n = 96	Other AEs: Mental status changes...
25 mg 1 times / day multiple, oral Studied dose	unhealthy, mean age 43.2 years n = 16	Other AEs: Dry mouth, Sleepiness...
75 mg 1 times / day multiple, oral Recommended	unhealthy, mean age 55 years n = 27	Disc. AE: Drowsiness, Dry mouth... Other AEs: Drowsiness, Nausea...

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AEs

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AE	Significance	Dose	Population
Agitation	20%	100 mg 1 times / day single, intravenous Studied dose	healthy, 21 to 70 years n = 5
Drowsiness	20%	100 mg 1 times / day single, intravenous Studied dose	healthy, 21 to 70 years n = 5
Dry mouth	20%	100 mg 1 times / day single, intravenous Studied dose	healthy, 21 to 70 years n = 5
Language disorder	20%	100 mg 1 times / day single, intravenous Studied dose	healthy, 21 to 70 years n = 5
Bradycardia	grade 3, 20% Disc. AE	100 mg 1 times / day single, intravenous Studied dose	healthy, 21 to 70 years n = 5

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737 inhibitor 1,587	substrate 1,037	substrate 1,217 inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C19 1,478 CYP2C8 911 OCT1 512 OCT2 647	CYP1A2 1,054 CYP2C19 991 CYP2B6 664 UGT2B10 127 UGT1A4 347

Drug as perpetrator

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Target	Modality	Activity
OCT2 648	inhibitor 3,277	yes [IC50 14 uM]
OCT1 543	inhibitor 3,277	yes [IC50 6.99 uM]
CYP3A4 1,925	inhibitor 3,277	yes [IC50 8.8 uM]
CYP2C8 965	inhibitor 3,277	yes [Inhibition 200 uM]
CYP2D6 1,891	inhibitor 3,277	yes [Ki 31 uM]

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Drug as victim

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Target	Modality	Activity
CYP1A2 1,054	substrate 3,367	no
CYP2C19 991	substrate 3,367	no
CYP2B6 664	substrate 3,367	yes
CYP2C9 1,037	substrate 3,367	yes
CYP2D6 1,217	substrate 3,367	yes

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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
ChEBI	CHEBI:2666	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:2666
MolPort	MolPort-001-662-651	https://www.molport.com/shop/molecule-link/MolPort-001-662-651
ZINC	ZINC000000968257	http://zinc15.docking.org/substances/ZINC000000968257
eMolecules	739635	https://www.emolecules.com/cgi-bin/more?vid=739635

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PubMed

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Title	Date	PubMed
Inhibition of HIV replication by neuroleptic agents and their potential use in HIV infected patients with AIDS related dementia.	2000 Apr	10773489
Antidepressants upregulate messenger RNA levels of the neuroprotective enzyme superoxide dismutase (SOD1).	2000 Jan	10721683
Block of rat brain recombinant SK channels by tricyclic antidepressants and related compounds.	2000 Jul 28	10915830
Prolonged QT interval and torsades de pointes caused by the combination of fluconazole and amitriptyline.	2000 Mar	10750939
Amitriptyline and somnambulism.	2000 Oct	11054994

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Patents

Sample Use Guides

In Vivo Use Guide

For outpatients, 75 mg of amitriptyline HCl a day in divided doses. If necessary, this may be increased to a total of 150 mg per day. An alternate method of initiating therapy in outpatients is to begin with 50 to 100 mg amitriptyline HCl at bedtime. This may be increased by 25 or 50 mg as necessary in the bedtime dose to a total of 150 mg per day. Hospitalized patients may require 100 mg a day initially. This can be increased gradually to 200 mg a day if necessary up to 300 mg a day. Not recommended for patients under 12 years of age

Route of Administration: Oral

In Vitro Use Guide

Amitriptyline was used at 40 uM in isolated rat hepatocytes for 60,120,180 min.

Substance Class	Chemical
Record UNII	1806D8D52K
Record Status	`Validated (UNII)`
Record Version

Show entries

Name

Type

Language

AMITRIPTYLINE

Official Name

English

1-PROPANAMINE, 3-(10,11-DIHYDRO-5H-DIBENZO(A,D)CYCLOHEPTEN-5-YLIDENE)-N,N-DIMETHYL-

Systematic Name

English

LAROXYL

Brand Name

English

3-(10,11-DIHYDRO-5H-DIBENZO(A,D)CYCLOHEPTEN-5-YLIDENE)-N,N-DIMETHYL-1-PROPANAMINE

Systematic Name

English

AMITRIPTYLINE [USP IMPURITY]

Common Name

English

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Classification Tree

Code System

Code

Antidepressants in combination with psycholeptics

WHO-ATC

N06CA01

Medicines used in mood disorders

WHO-ESSENTIAL MEDICINES LIST

24.2.1

Designated

FDA ORPHAN DRUG

288809

Non-selective monoamine reuptake inhibitors

WHO-VATC

QN06AA09

Antidepressant

LIVERTOX

NBK548410

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Code System

Code

Type

Description

MESH

D000639

PRIMARY

LACTMED

Amitriptyline

PRIMARY

SMS_ID

100000092029

PRIMARY

WIKIPEDIA

AMITRIPTYLINE

PRIMARY

HSDB

3007

PRIMARY

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Show entries

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					8E4LAA4357

CYTOCHROME P450 2D6

METABOLIC ENZYME -> SUBSTRATE

Comments:

Metabolizing reaction by CYP2D6: N-demethylation


					2Z7LDE78YX

URIDINE DIPHOSPHATE GLUCURONOSYLTRANSFERASE 1A4

METABOLIC ENZYME -> SUBSTRATE


					6D53G0FD0Z

PLASMA PROTEIN FRACTION (HUMAN)

BINDER->LIGAND

Interaction Type:

BINDING

Amount:

95 % (average)


					NQI5D806LC

5-HYDROXYTRYPTAMINE RECEPTOR 2A

TARGET -> INHIBITOR


					ONY583280Z

OCT-1

TRANSPORTER -> INHIBITOR

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					CD85QI7QOV

10-HYDROXYNORTRIPTYLINE, (E)-

METABOLITE -> PARENT

Amount:

95 % (average)


					V05NFJ590Z

10-HYDROXYAMITRIPTYLINE, (Z)-

METABOLITE -> PARENT

Qualification:

URINE


					BL03SY4LXB

NORTRIPTYLINE

METABOLITE ACTIVE -> PARENT

Interaction Type:

MAJOR


					O9152DHW61

10-HYDROXYAMITRIPTYLINE

METABOLITE -> PARENT

Amount:


					EO3CW810PB

3-HYDROXYAMITRIPTYLINE

METABOLITE -> PARENT

Qualification:

URINE

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Type

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					0VE05JYS2P

CYCLOBENZAPRINE HYDROCHLORIDE

PARENT -> IMPURITY

Interaction Type:

CHROMATOGRAPHIC PURITY (HPLC/UV)

Qualification:

USP

Amount:

[<0.15] PERCENT PEAK AREA (limits)


					00FN6IH15D

NORTRIPTYLINE HYDROCHLORIDE

PARENT -> IMPURITY

Comments:

UNSPECIFIED

Qualification:

EP

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Related Record

Type

Details


					1806D8D52K

AMITRIPTYLINE

ACTIVE MOIETY

Amount:

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Name	Property Type	Amount	Parameters
Volume of Distribution	PHARMACOKINETIC	[18 to 22] Liters/Kilogram (average)

Volume of Distribution	PHARMACOKINETIC	VARIES WIDELY

MAXIMUM TOLERATED DOSE	TOXICITY	150 mg/day (average) DEPRESSION, OUTPATIENTS	DEPRESSION, INPATIENTS: 300 MG/DAY

Route of Elimination	PHARMACOKINETIC	RENAL: ONE-HALF TO ONE-THIRD OF THE DOSE, ALMOST ENTIRELY AS METABOLITES, LITTLE AMOUNT AS UNCHANGED

Biological Half-life	PHARMACOKINETIC	[13 to 36] hours (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