TIAGABINE HYDROCHLORIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C20H25NO2S2.ClH
Molecular Weight	412.009
Optical Activity	( - )
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

Cl.CC1=C(SC=C1)C(=CCCN2CCC[C@H](C2)C(O)=O)C3=C(C)C=CS3

InChI

InChIKey=YUKARLAABCGMCN-PKLMIRHRSA-N

InChI=1S/C20H25NO2S2.ClH/c1-14-7-11-24-18(14)17(19-15(2)8-12-25-19)6-4-10-21-9-3-5-16(13-21)20(22)23;/h6-8,11-12,16H,3-5,9-10,13H2,1-2H3,(H,22,23);1H/t16-;/m1./s1

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020646s021lbl.pdf
Curator's Comment: description was created based on several sources, including https://www.drugs.com/pro/tiagabine.html | https://www.drugbank.ca/drugs/DB00906 | http://reference.medscape.com/drug/gabitril-tiagabine-343022 | https://www.ncbi.nlm.nih.gov/pubmed/8595791 | https://www.ncbi.nlm.nih.gov/pubmed/16420077 | https://www.ncbi.nlm.nih.gov/pubmed/15519917

Tiagabine (trade name Gabitril) is an anticonvulsant medication used in the treatment of Partial Seizures. The precise mechanism by which Tiagabine exerts its antiseizure effect is unknown, although it is believed to be related to its ability to enhance the activity of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Tiagabine binds to recognition sites associated with the GABA uptake carrier. It is thought that, by this action, Tiagabine blocks GABA uptake into presynaptic neurons, permitting more GABA to be available for receptor binding on the surfaces of post-synaptic cells. Tiagabine is approved by U.S. Food and Drug Administration (FDA) as an adjunctive treatment for partial seizures in individuals of age 12 and up. It may also be prescribed off-label by physicians to treat anxiety disorders and panic disorder as well as neuropathic pain (including fibromyalgia). For anxiety and neuropathic pain, tiagabine is used primarily to augment other treatments. Tiagabine may be used alongside selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, or benzodiazepines for anxiety, or antidepressants, gabapentin, other anticonvulsants, or opioids for neuropathic pain. The most common side effect of tiagabine is dizziness. Other side effects that have been observed with a rate of statistical significance relative to placebo include asthenia, somnolence, nervousness, memory impairment, tremor, headache, diarrhea, and depression.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
GABA transporter 1 11 Target ID: CHEMBL1903 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8057281	Inhibitor 8504	70.0 nM [IC50]
GABA transporter 3 7 Target ID: CHEMBL5208 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8057281	Inhibitor 8504	917.0 µM [IC50]
Betaine transporter 4 Target ID: CHEMBL3715 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8057281	Inhibitor 8504	1670.0 µM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Partial seizures 8 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020646s021lbl.pdf	Primary	Approved 8583	GABITRIL Approved Use GABITRIL (tiagabine hydrochloride) is indicated as adjunctive therapy in adults and children 12 years and older in the treatment of partial seizures. Launch Date 1997
Anxiety 275 Sources: https://clinicaltrials.gov/ct2/show/NCT00236015	Primary	Phase III 665	GABITRIL Approved Use GABITRIL (tiagabine hydrochloride) is indicated as adjunctive therapy in adults and children 12 years and older in the treatment of partial seizures. Launch Date 1997
Cocaine-related disorders 19 Sources: https://clinicaltrials.gov/ct2/show/NCT00129298	Primary	Phase II 1147	GABITRIL Approved Use GABITRIL (tiagabine hydrochloride) is indicated as adjunctive therapy in adults and children 12 years and older in the treatment of partial seizures. Launch Date 1997

C_max

Value	Dose	Co-administered	Analyte	Population
552 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/7555975	24 mg single, oral dose: 24 mg route of administration: Oral experiment type: SINGLE co-administered:		TIAGABINE blood	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
265 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/7555975	10 mg 1 times / day multiple, oral dose: 10 mg route of administration: Oral experiment type: MULTIPLE co-administered:		TIAGABINE blood	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
2190 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/7555975	24 mg single, oral dose: 24 mg route of administration: Oral experiment type: SINGLE co-administered:		TIAGABINE blood	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
826 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/7555975	10 mg 1 times / day multiple, oral dose: 10 mg route of administration: Oral experiment type: MULTIPLE co-administered:		TIAGABINE blood	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
7.3 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/7555975	24 mg single, oral dose: 24 mg route of administration: Oral experiment type: SINGLE co-administered:		TIAGABINE blood	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
6.5 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/7555975	10 mg 1 times / day multiple, oral dose: 10 mg route of administration: Oral experiment type: MULTIPLE co-administered:		TIAGABINE blood	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

Doses

Dose	Population	Adverse events
320 mg single, oral Overdose Dose: 320 mg Route: oral Route: single Dose: 320 mg Sources: https://pubmed.ncbi.nlm.nih.gov/7670769	unhealthy, 30 Health Status: unhealthy Age Group: 30 Sex: M Sources: https://pubmed.ncbi.nlm.nih.gov/7670769	Disc. AE: Drowsiness, Coma... AEs leading to discontinuation/dose reduction: Drowsiness Coma (grade 3) Sources: https://pubmed.ncbi.nlm.nih.gov/7670769
72 mg single, oral Overdose Dose: 72 mg Route: oral Route: single Dose: 72 mg Sources: https://pubmed.ncbi.nlm.nih.gov/15388215	unhealthy, 46 Health Status: unhealthy Age Group: 46 Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/15388215	Disc. AE: Stupor, Confusion... AEs leading to discontinuation/dose reduction: Stupor Confusion Sources: https://pubmed.ncbi.nlm.nih.gov/15388215

AEs

AE	Significance	Dose	Population
Drowsiness	Disc. AE	320 mg single, oral Overdose Dose: 320 mg Route: oral Route: single Dose: 320 mg Sources: https://pubmed.ncbi.nlm.nih.gov/7670769	unhealthy, 30 Health Status: unhealthy Age Group: 30 Sex: M Sources: https://pubmed.ncbi.nlm.nih.gov/7670769
Coma	grade 3 Disc. AE	320 mg single, oral Overdose Dose: 320 mg Route: oral Route: single Dose: 320 mg Sources: https://pubmed.ncbi.nlm.nih.gov/7670769	unhealthy, 30 Health Status: unhealthy Age Group: 30 Sex: M Sources: https://pubmed.ncbi.nlm.nih.gov/7670769
Confusion	Disc. AE	72 mg single, oral Overdose Dose: 72 mg Route: oral Route: single Dose: 72 mg Sources: https://pubmed.ncbi.nlm.nih.gov/15388215	unhealthy, 46 Health Status: unhealthy Age Group: 46 Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/15388215
Stupor	Disc. AE	72 mg single, oral Overdose Dose: 72 mg Route: oral Route: single Dose: 72 mg Sources: https://pubmed.ncbi.nlm.nih.gov/15388215	unhealthy, 46 Health Status: unhealthy Age Group: 46 Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/15388215

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1946		substrate 1388	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP 110 UGT 45	CYP2C9/10 4 CYP1A2 1197 P-gp 2052 CYP2C19 1119	rCYP2B 5

Drug as perpetrator

Target	Modality	Activity
CYP 150	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/11092610/	unlikely
UGT 70	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/11092610/	unlikely
rCYP2B 9	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020646ap_gabitril_phrmr.pdf#page=14 Page: 14.0	yes

Drug as victim

Target	Modality	Activity
CYP1A2 1197	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020646ap_gabitril_phrmr.pdf#page=13 Page: 13.0	likely
CYP2C19 1119	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020646ap_gabitril_phrmr.pdf#page=14 Page: 14.0	likely
CYP2D6 1388	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020646ap_gabitril_phrmr.pdf#page=13 Page: 13.0	likely
CYP2C9/10 4	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020646ap_gabitril_phrmr.pdf#page=13 Page: 13.0	no
P-gp 2052	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/29548981/	no
CYP3A4 1946	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020646ap_gabitril_phrmr.pdf#page=13 Page: 13.0	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://www.mdpi.com/1420-3049/26/12/3522

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:9586	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:9586
eMolecules	902575	https://www.emolecules.com/cgi-bin/more?vid=902575
MolPort	MolPort-006-167-658	https://www.molport.com/shop/molecule-link/MolPort-006-167-658
ZINC	ZINC000003831531	http://zinc15.docking.org/substances/ZINC000003831531

PubMed

Title	Date	PubMed
Comparison of antiepileptic drugs tiagabine, lamotrigine, and gabapentin in mouse models of acute, prolonged, and chronic nociception.	2002-09	12183677
An open case series on the utility of tiagabine as an augmentation in refractory bipolar outpatients.	2002-09	12167526
[(3)H]Tiagabine binding to GABA transporter-1 (GAT-1) in suicidal depression.	2002-09	12167498
New antiepileptic drugs in childhood.	2002-09	12094136
Selective suppression of hippocampal region hyperexcitability related to seizure susceptibility in epileptic El mice by the GABA-transporter inhibitor tiagabine.	2002-08-30	12176163
Neuroprotective effect of tiagabine in transient forebrain global ischemia: an in vivo microdialysis, behavioral, and histological study.	2002-08-16	12137918
Correlation between anticonvulsant activity and inhibitory action on glial gamma-aminobutyric acid uptake of the highly selective mouse gamma-aminobutyric acid transporter 1 inhibitor 3-hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazole and its N-alkylated analogs.	2002-08	12130726
Tiagabine, a gamma-amino-butyric acid transporter inhibitor impairs spatial learning of rats in the Morris water-maze.	2002-07-18	12110474
Aggravation of partial seizures by antiepileptic drugs: is there evidence from clinical trials?	2002-07-09	12105311
Tiagabine overdose can induce convulsive status epilepticus.	2002-07	12102683
Effects of antiepileptic drugs on visual function, with special reference to Vigabatrin.	2002-06	12059879
Tiagabine-related non-convulsive status epilepticus in partial epilepsy: three case reports and a review of the literature.	2002-06	12027571
Anxiolytic-like effects of acute and chronic GABA transporter inhibition in rats.	2002-05	12111474
[New antiepileptic drugs: new therapeutic options].	2002-05	11997751
Contribution of GABAergic cortical circuitry in shaping somatosensory evoked scalp responses: specific changes after single-dose administration of tiagabine.	2002-05	11976045
Effects of tiagabine, a gamma-aminobutyric acid re-uptake inhibitor, on normal rat bladder function.	2002-05	11956486
The 'number needed to treat' with levetiracetam (LEV): comparison with the other new antiepileptic drugs (AEDs).	2002-04	12185762
Third generation anticonvulsants in bipolar disorder: a review of efficacy and summary of clinical recommendations.	2002-04	12000201
Free-choice ethanol consumption under the influence of GABAergic drugs in rats.	2002-04	11981120
Occurrence of psychosis in patients with epilepsy randomized to tiagabine or placebo treatment.	2002-04	11952769
The importance of drug interactions in epilepsy therapy.	2002-04	11952767
Some common issues in the use of antiepileptic drugs.	2002-03	12170391
Recurrent complex partial status epilepticus associated with tiagabine rechallenge.	2002-03	12094558
Tiagabine in glial tumors.	2002-03	11948010
Visual field defects.	2002-03	11945104
[Adult GM2 gangliosidosis: improvement of ataxia with GABAergic drugs].	2002-03	11927106
New antiepileptic drugs: review on drug interactions.	2002-02	11805729
Marketed new antiepileptic drugs: are they better than old-generation agents?	2002-02	11805726
Effects of tiagabine and diazepam on operant ethanol self-administration in the rat.	2002-01	11925051
Non-convulsive status epilepticus induced by tiagabine in a patient with pseudoseizure.	2002-01	11888262
The use of tiagabine in affective disorders.	2002-01	11819159
Appropriate use of medications for seizures. Guiding principles on the path of efficacy.	2002-01	11810752
Bi-directional transport of GABA in human embryonic kidney (HEK-293) cells stably expressing the rat GABA transporter GAT-1.	2002-01	11786484
New and emerging prophylactic agents for migraine.	2002	12153333
Tiagabine add-on for drug-resistant partial epilepsy.	2002	12137637
Treatment of epilepsy in women of reproductive age: pharmacokinetic considerations.	2002	12102641
Mood disorders in patients with epilepsy: epidemiology and management.	2002	11994019
Cellular mechanisms of pharmacoresistance in slices from epilepsy surgery.	2002	11990776
Interactions between antiepileptic drugs and hormonal contraception.	2002	11945109
Effect of antiepileptic drugs on cognitive function in individuals with epilepsy: a comparative review of newer versus older agents.	2002	11893228
Anticonvulsants: aspects of their mechanisms of action.	2002	11888234
Seizures in HIV-seropositive individuals: epidemiology and treatment.	2002	11825100
Increased [(3)H]tiagabine binding to GAT-1 in the cingulate cortex in schizophrenia.	2002	11803235
[Monitoring of renal function in epileptic children and teenagers treated with valproic acid or carbamazepine in concomitant therapy with tiagabine].	2001-12	11899842
Clinical pharmacology and therapeutic use of the new antiepileptic drugs.	2001-12	11860529
Treatment of painful sensory neuropathy with tiagabine: a pilot study.	2001-12	11794716
Second generation anticonvulsant medications: their use in children.	2001-04	11885112
Clinical evaluation of Gabitril and Lamictal for drug-resistant epilepsy in adults.	2001	11977339
[New antiepileptic drugs in childhood epilepsies: indications and limits].	2001	11827845
[Hormonal contraception and epilepsy].	2001	11799750

Patents

Sample Use Guides

In Vivo Use Guide

12-22 mg/day PO divided q8-12hr

Route of Administration: Oral

In Vitro Use Guide

The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) proliferation assay is based on conversion by mitochondrial dehydrogenases of the substrate containing a tetrazolium ring into blue formazan, detectable spectrophotometrically (10). The level of blue formazan is then used as indirect index of cell density. The astrocytes were set up in flat-bottomed 200-μl microplates, incubated at 37◦C in a humidified 5% CO2/95% air mixture, and treated with 1, 10, 50, and 100 μg/ml of Tiagabine for 48 h. Four hours before the end of the culture, 20 μl of 0.5% 3-(4,5-dimethylthiazol-2-yl)diphenyltetrazolium bromide in phosphate-buffered saline (PBS) was added to each microwell. After the incubation with the reagent, the supernatant was removed and replaced with 100 μl of acidified isopropanol and 20 μl of 3% (wt/vol) sodium dodecylsulfate (SDS) in water. The optical density of each sample was measured with a microplate spectrophotometer reader (Titertek Multiskan, Flow Laboratories) at 570 nm, and four replicates were performed for each sample.

Name

Type

Language

GABITRIL

Preferred Name

English

TIAGABINE HYDROCHLORIDE

Official Name

English

3-PIPERIDINECARBOXYLIC ACID, 1-(4,4-BIS(3-METHYL-2-THIENYL)-3-BUTENYL)-, HYDROCHLORIDE, (R)-

Systematic Name

English

ABBOTT-70569.1

Code

English

NNC-050328

Code

English

TIAGABINE HCL

Common Name

English

Tiagabine hydrochloride [WHO-DD]

Common Name

English

TIAGABINE HYDROCHLORIDE [VANDF]

Common Name

English

TIAGABINE HYDROCHLORIDE [MART.]

Common Name

English

NO-05-0328

Code

English

ABBOTT-705691

Code

English

TIAGABINE HYDROCHLORIDE [USP MONOGRAPH]

Common Name

English

ABBOTT-70569.HCL

Code

English

ABT-569

Code

English

TIAGABINE HYDROCHLORIDE [USAN]

Common Name

English

TIAGABINE HYDROCHLORIDE [USP-RS]

Common Name

English

TIAGABINE HYDROCHLORIDE [MI]

Common Name

English

Gabatril

Common Name

English

NO-050328

Code

English

TIAGABINE HYDROCHLORIDE [ORANGE BOOK]

Common Name

English

NNC-05-0328

Code

English

ABBOTT-70569 HYDROCHLORIDE

Code

English

Code System Code Type Description

USAN

II-38