TERBINAFINE HYDROCHLORIDE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C21H25N.ClH
Molecular Weight	327.891
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

Cl.CN(C\C=C\C#CC(C)(C)C)CC1=CC=CC2=CC=CC=C12

InChI

InChIKey=BWMISRWJRUSYEX-SZKNIZGXSA-N

InChI=1S/C21H25N.ClH/c1-21(2,3)15-8-5-9-16-22(4)17-19-13-10-12-18-11-6-7-14-20(18)19;/h5-7,9-14H,16-17H2,1-4H3;1H/b9-5+;

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020539s029,022071s013lbl.pdf

Terbinafine (brand name Lamisil, Terbisil, Terboderm and others) is an antifungal medication used to treat ringworm and fungal nail infections. Terbinafine inhibits ergosterol synthesis by inhibiting squalene epoxidase, an enzyme that is part of the fungal cell membrane synthesis pathway. Because terbinafine prevents the conversion of squalene to lanosterol, ergosterol cannot be synthesized. This is thought to change cell membrane permeability, causing fungal cell lysis. Many side effects and adverse drug reactions have been reported with oral terbinafine hydrochloride possibly due to its extensive biodistribution and the often extended durations involved in antifungal treatment (longer than two months).

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Squalene monooxygenase 10 Target ID: CHEMBL1888 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21229992	Inhibitor 8297		30.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Onychomycosis 18 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020539s029,022071s013lbl.pdf	Curative		Approved 8429	LAMISIL Approved Use Uses cures most athlete’s foot (tinea pedis) between the toes.Effectiveness on the bottom or sides of foot is unknown. cures most jock itch (tinea cruris) and ringworm (tinea corporis) relieves itching, burning, cracking and scaling which accompany these conditions Launch Date 1998

C_max

Value	Dose	Analyte	Population
1.7 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8593011/	250 mg 1 times / day multiple, oral dose: 250 mg route of administration: Oral experiment type: MULTIPLE co-administered:	TERBINAFINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
1.34 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8593011/	250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered:	TERBINAFINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
1 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020539s021lbl.pdf	250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered:	TERBINAFINE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
10.48 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8593011/	250 mg 1 times / day multiple, oral dose: 250 mg route of administration: Oral experiment type: MULTIPLE co-administered:	TERBINAFINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
4.74 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8593011/	250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered:	TERBINAFINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
4.56 μg × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020539s021lbl.pdf	250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered:	TERBINAFINE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
16.5 day EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8593011/	250 mg 1 times / day multiple, oral dose: 250 mg route of administration: Oral experiment type: MULTIPLE co-administered:		TERBINAFINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
36 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020539s021lbl.pdf	250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered:		TERBINAFINE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
1% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020539s021lbl.pdf	250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered:		TERBINAFINE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
500 mg 2 times / day multiple, oral Highest studied dose Dose: 500 mg, 2 times / day Route: oral Route: multiple Dose: 500 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/16445509 Page: p.155	unhealthy, 31 n = 27 Health Status: unhealthy Condition: Eumycetoma Age Group: 31 Sex: M+F Population Size: 27 Sources: https://pubmed.ncbi.nlm.nih.gov/16445509 Page: p.155	Disc. AE: Neutropenia, Neutropenia... AEs leading to discontinuation/dose reduction: Neutropenia (7.4%) Neutropenia (3.7%) Glutamic-oxaloacetic transaminase increased (3.7%) Serum glutamic-pyruvic transaminase increased (3.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/16445509 Page: p.155
5 g single, oral Overdose Dose: 5 g Route: oral Route: single Dose: 5 g Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020539s029,022071s013lbl.pdf Page: p.6	unhealthy Health Status: unhealthy Condition: Fingernail onychomycosis\|Toenail onychomycosis Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020539s029,022071s013lbl.pdf Page: p.6	Other AEs: Nausea, Vomiting... Other AEs: Nausea Vomiting Abdominal pain Dizziness Rash Urination frequency of Headache Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020539s029,022071s013lbl.pdf Page: p.6
1 % 1 times / day multiple, topical Recommended Dose: 1 %, 1 times / day Route: topical Route: multiple Dose: 1 %, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/20846s001lbl.pdf Page: p.8	unhealthy Health Status: unhealthy Condition: Tinea\|tinea pedis\|tinea corporis\|tinea cruris Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/20846s001lbl.pdf Page: p.8	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/20846s001lbl.pdf Page: p.8
250 mg 1 times / day multiple, oral Recommended Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020539s029,022071s013lbl.pdf Page: p.3	unhealthy n = 465 Health Status: unhealthy Condition: Fingernail onychomycosis\|Toenail onychomycosis Population Size: 465 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020539s029,022071s013lbl.pdf Page: p.3	Disc. AE: Headache... AEs leading to discontinuation/dose reduction: Headache (0.2%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020539s029,022071s013lbl.pdf Page: p.3
250 mg 1 times / day multiple, oral Recommended Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020539s029,022071s013lbl.pdf Page: p.4	unhealthy n = 465 Health Status: unhealthy Condition: Fingernail onychomycosis\|Toenail onychomycosis Population Size: 465 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020539s029,022071s013lbl.pdf Page: p.4	Disc. AE: Diarrhea, Dyspepsia... AEs leading to discontinuation/dose reduction: Diarrhea (0.6%) Dyspepsia (0.4%) Abdominal pain (0.4%) Nausea (0.2%) Rash (0.9%) Pruritus (0.2%) Liver enzyme abnormal (0.2%) Taste disturbance (0.2%) Visual disturbance (0.9%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020539s029,022071s013lbl.pdf Page: p.4
250 mg 1 times / day multiple, oral Recommended Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020539s029,022071s013lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Fingernail onychomycosis\|Toenail onychomycosis Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020539s029,022071s013lbl.pdf Page: p.1	Disc. AE: Liver failure, Taste disturbance... AEs leading to discontinuation/dose reduction: Liver failure Taste disturbance (severe) Smell alteration Depressive symptom Neutropenia (severe) Stevens-Johnson syndrome Toxic epidermal necrolysis Erythema multiforme Exfoliative dermatitis Bullous dermatitis Drug reaction with eosinophilia and systemic symptoms Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020539s029,022071s013lbl.pdf Page: p.1
250 mg 1 times / day multiple, oral Recommended Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020539s029,022071s013lbl.pdf Page: p.3	unhealthy Health Status: unhealthy Condition: Fingernail onychomycosis\|Toenail onychomycosis Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020539s029,022071s013lbl.pdf Page: p.3	Disc. AE: Lupus erythematosus, Thrombotic microangiopathy... AEs leading to discontinuation/dose reduction: Lupus erythematosus Thrombotic microangiopathy Thrombotic thrombocytopenic purpura Hemolytic uremic syndrome Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020539s029,022071s013lbl.pdf Page: p.3

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737	substrate 1037	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP1A2 1054 CYP2C8 693 CYP2C19 991 CYP2B6 664

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP2D6 1891	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/10460803/ Page: -	yes [Ki 0.03 uM]		yes (co-administration study) Comment: In studies in healthy subjects characterized as extensive metabolizers of dextromethorphan (antitussive drug and CYP2D6 probe substrate), terbinafine increases the dextromethorphan/ dextrorphan metabolite ratio in urine by 16- to 97-fold on average Sources: https://pubmed.ncbi.nlm.nih.gov/10460803/ Page: -

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP1A2 1054	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10460803/ Page: -	yes
CYP1A2 1054	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10460803/ Page: -	yes	Hydroxyterbinafine 4
CYP2B6 664	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10460803/ Page: -	yes	Hydroxyterbinafine 4
CYP2C19 991	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10460803/ Page: -	yes
CYP2C19 991	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10460803/ Page: -	yes	Hydroxyterbinafine 4
CYP2C8 693	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10460803/ Page: -	yes
CYP2C8 693	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10460803/ Page: -	yes	Hydroxyterbinafine 4
CYP2C9 1037	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10460803/ Page: -	yes	Hydroxyterbinafine 4
CYP3A4 1737	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10460803/ Page: -	yes	Hydroxyterbinafine 4
CYP2C9 1037	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10460803/ Page: -	yes		yes (co-administration study) Comment: Coadministration of a single dose of fluconazole (100 mg) with a single dose of terbinafine resulted in a 52% and 69% increase in terbinafine Cmax and AUC, respectively. Fluconazole is an inhibitor of CYP2C9 and CYP3A enzymes. Based on this finding, it is likely that other inhibitors of both CYP2C9 and CYP3A4 (e.g., ketoconazole, amiodarone) may also lead to a substantial increase in the systemic exposure (Cmax and AUC) of terbinafine when concomitantly administered. Sources: https://pubmed.ncbi.nlm.nih.gov/10460803/ Page: -
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020539s033lbl.pdf#page=5 Page: 5.0	yes		yes (co-administration study) Comment: Coadministration of a single dose of fluconazole (100 mg) with a single dose of terbinafine resulted in a 52% and 69% increase in terbinafine Cmax and AUC, respectively. Fluconazole is an inhibitor of CYP2C9 and CYP3A enzymes. Based on this finding, it is likely that other inhibitors of both CYP2C9 and CYP3A4 (e.g., ketoconazole, amiodarone) may also lead to a substantial increase in the systemic exposure (Cmax and AUC) of terbinafine when concomitantly administered. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020539s033lbl.pdf#page=5 Page: 5.0

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://pubmed.ncbi.nlm.nih.gov/12729675/ Page: -

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:9448	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:9448
MolPort	MolPort-002-507-761	https://www.molport.com/shop/molecule-link/MolPort-002-507-761
Selleck Chemicals	Terbinafine(Lamisil)	http://www.selleckchem.com/products/Terbinafine(Lamisil).html
ZINC	ZINC000001530981	http://zinc15.docking.org/substances/ZINC000001530981
eMolecules	902552	https://www.emolecules.com/cgi-bin/more?vid=902552

PubMed

Title	Date	PubMed
Synthesis and antifungal activity of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphtha lenemethanamine (SF 86-327) and related allylamine derivatives with enhanced oral activity.	1984 Dec	6502589
Antifungal activity of the allylamine derivative terbinafine in vitro.	1987 Sep	3674847
Pharmacology of the allylamines.	1990 Oct	2229523
Terbinafine: mode of action and properties of the squalene epoxidase inhibition.	1992 Feb	1543672
New drug developments for opportunistic infections in immunosuppressed patients: Pneumocystis carinii.	1995 Nov 24	7490723
[Ageusia caused by terbinafine].	1995 Sep 9	7475473
Comparative study of antifungal activity of sertaconazole, terbinafine, and bifonazole against clinical isolates of Candida spp., Cryptococcus neoformans and dermatophytes.	1997 Nov-Dec	9395851
Safety of oral terbinafine: results of a postmarketing surveillance study in 25,884 patients.	1997 Oct	9382559
In vitro activities of terbinafine against cutaneous isolates of Candida albicans and other pathogenic yeasts.	1998 May	9593126
Randomized double-blind comparison of short-term itraconazole and terbinafine therapy for toenail onychomycosis.	1999 May	10384922
Effects of sterol inhibitors on the ATP content of Pneumocystis carinii.	1999 Sep-Oct	10519292
Synergy between 6-amino-2-n-pentylthiobenzothiazole and ergosterol biosynthesis-inhibiting antimycotics against Candida albicans in vitro.	2000 Jul	10854813
Inhibitors of sterol biosynthesis and amphotericin B reduce the viability of pneumocystis carinii f. sp. carinii.	2000 Jun	10817720
Potent synergism of the combination of fluconazole and cyclosporine in Candida albicans.	2000 Sep	10952582
Synergistic interaction of terbinafine with triazoles or amphotericin B against Aspergillus species.	2001 Feb	11270414
Ergosterol biosynthesis inhibitors become fungicidal when combined with calcineurin inhibitors against Candida albicans, Candida glabrata, and Candida krusei.	2003 Mar	12604527
Terbinafine resistance in a pleiotropic yeast mutant is caused by a single point mutation in the ERG1 gene.	2003 Sep 26	12963042
Ursodeoxycholic acid for terbinafine-induced toxic hepatitis.	2004 Jun	15122001
[Colestasic toxic hepatitis caused by terbinafine: case report].	2004 Oct-Dec	15614306
Safety and tolerability of oral antifungal agents in the treatment of fungal nail disease: a proven reality.	2005 Dec	18360572
Prediction of genotoxicity of chemical compounds by statistical learning methods.	2005 Jun	15962942
Terbinafine-induced acute generalized exanthematous pustulosis.	2008 Apr	18833041
Synthesis of new N-phenylpyrazole derivatives with potent antimicrobial activity.	2008 Apr 15	18313934
Antifungal triterpene glycosides from the sea cucumber Bohadschia marmorata.	2009 Feb	19096993
Terbinafine: a pharmacological and clinical review.	2009 Nov	19874252
Fungicide activity of 5-(4-chlorobenzylidene)-(Z)-2-dimethylamino-1,3-thiazol-4-one against Cryptococcus neoformans.	2010 Jan	19927310
Update on antifungal therapy with terbinafine.	2010 Jun	20461049
Efficient synthesis of novel 1,2,4-triazole fused acyclic and 21-28 membered macrocyclic and/or lariat macrocyclic oxaazathia crown compounds with potential antimicrobial activity.	2010 Nov	20875694
Isavuconazole: a comprehensive review of spectrum of activity of a new triazole.	2010 Nov	20524153
Terbinafine stimulates the pro-inflammatory responses in human monocytic THP-1 cells through an ERK signaling pathway.	2010 Oct 23	20816994
Development of a highly sensitive cytotoxicity assay system for CYP3A4-mediated metabolic activation.	2011 Aug	21540358
Synthesis and in-vitro antimicrobial activity of secondary and tertiary amines containing 2-chloro-6-methylquinoline moiety.	2011 Jul	21618272
In vitro antifungal susceptibility of clinically relevant species belonging to Aspergillus section Flavi.	2013 Apr	23335742
Assessment of phytochemicals, antimicrobial and cytotoxic activities of extract and fractions from Fagonia olivieri (Zygophyllaceae).	2013 Jul 10	23842440
Hippolachnin A, a new antifungal polyketide from the South China Sea sponge Hippospongia lachne.	2013 Jul 19	23829334
FDA-approved drugs and other compounds tested as inhibitors of human glutathione transferase P1-1.	2013 Sep 5	23769903
Genomic models of short-term exposure accurately predict long-term chemical carcinogenicity and identify putative mechanisms of action.	2014	25058030
A correlation between the in vitro drug toxicity of drugs to cell lines that express human P450s and their propensity to cause liver injury in humans.	2014 Jan	24085192
Identification and antifungal susceptibility of fungi isolated from dermatomycoses.	2014 May	23556501
Arachidonic acid affects biofilm formation and PGE2 level in Candida albicans and non-albicans species in presence of subinhibitory concentration of fluconazole and terbinafine.	2014 May-Jun	24389279
Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis.	2015 May 18	25811541

Patents

Sample Use Guides

In Vivo Use Guide

Prior to administering, evaluate patients for evidence of chronic or active liver disease. Fingernail onychomycosis: One 250 mg tablet, once daily for 6 weeks. Toenail onychomycosis: One 250 mg tablet, once daily for 12 weeks.

Route of Administration: Oral

In Vitro Use Guide

TRB (Terbinafine) were diluted 100-fold in dimethyl sulfoxide to obtain stock solutions that were kept at -20ºC. The antifungals were diluted in RPMI-1640 medium (Sigma Chemical Co, Missouri, USA) at pH 7.0 buffered with 0.16 M morpholinepropanesulfonic acid to obtain final concentrations ranging from 0.03-16 μg/mL for TRB. The diluted antifungal suspensions were then added to 96-well microtitre trays. Next, each fungal suspension was inoculated into the appropriate well at final concentrations ranging from 0.5 x 10^3-2.5 x 10^3 CFU/mL. The minimum inhibitory concentration (MIC) of each antifungal was determined by spectrophotometric reading at 492 nm following incubation at 35ºC for 72 h.

Name

Type

Language

TERBINAFINE HYDROCHLORIDE

Common Name

English

LAMISIL

Brand Name

English

TERBINAFINE (AS HYDROCHLORIDE)

Common Name

English

TERBINAFINE HYDROCHLORIDE [EP MONOGRAPH]

Common Name

English

NSC-759113

Code

English

TERBINAFINE HYDROCHLORIDE [USP MONOGRAPH]

Common Name

English

TERBINAFINE HYDROCHLORIDE [VANDF]

Common Name

English

BRAMIZIL

Brand Name

English

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthalenemethylamine, hydrochloride

Systematic Name

English

TERBINA

Brand Name

English

TERBINAFINE HYDROCHLORIDE [MI]

Common Name

English

TERBINE

Brand Name

English

BRAMAZIL

Brand Name

English

MUZONAL

Brand Name

English

TERBINAFINE HCL

Common Name

English

(2E)-N,6,6-TRIMETHYL-N-(NAPHTHALEN-1-YLMETHYL)HEPT-2-EN-4-YN-1-AMINE HYDROCHLORIDE

Systematic Name

English

TERBINAFINE HYDROCHLORIDE [USP-RS]

Common Name

English

Terbinafine hydrochloride [WHO-DD]

Common Name

English

TERBINAFINE HYDROCHLORIDE [MART.]

Common Name

English

TERBINAFINE HYDROCHLORIDE [JAN]

Common Name

English

1-NAPHTHALENEMETHANAMINE, N-(6,6-DIMETHYL-2-HEPTEN-4-YNYL)-N-METHYL-, (E)-, HYDROCHLORIDE

Common Name

English

TERBINAFINE HYDROCHLORIDE [ORANGE BOOK]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C514