Absorption, Distribution and Excretion
Tiagabine is nearly completely absorbed (>95%).
Approximately 2% of an oral dose of tiagabine is excreted unchanged, with 25% and 63% of the remaining dose excreted into the urine and feces, respectively, primarily as metabolites.
109 mL/min [Healthy subjects]
Absorption of tiagabine is rapid, with peak plasma concentrations occurring at approximately 45 minutes following an oral dose in the fasting state. Tiagabine is nearly completely absorbed (>95%), with an absolute oral bioavailability of about 90%. A high fat meal decreases the rate (mean T max was prolonged to 2.5 hours, and mean C max was reduced by about 40%) but not the extent (AUC) of tiagabine absorption.
The pharmacokinetics of tiagabine are linear over the single dose range of 2 to 24 mg. Following multiple dosing, steady state is achieved within 2 days.
Tiagabine is 96% bound to human plasma proteins, mainly to serum albumin and alpha1-acid glycoprotein over the concentration range of 10 ng/mL to 10,000 ng/mL. While the relationship between tiagabine plasma concentrations and clinical response is not currently understood, trough plasma concentrations observed in controlled clinical trials at doses from 30 to 56 mg/day ranged from <1 ng/mL to 234 ng/mL.
A diurnal effect on the pharmacokinetics of tiagabine was observed. Mean steady-state C min values were 40% lower in the evening than in the morning. Tiagabine steady-state AUC values were also found to be 15% lower following the evening tiagabine dose compared to the AUC following the morning dose.
For more Absorption, Distribution and Excretion (Complete) data for TIAGABINE (9 total), please visit the HSDB record page.

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Metabolism / Metabolites
Tiagabine is likely metabolized primarily by the 3A isoform subfamily of hepatic cytochrome P450.
Although the metabolism of tiagabine has not been fully elucidated, in vivo and in vitro studies suggest that at least two metabolic pathways for tiagabine have been identified in humans: 1) thiophene ring oxidation leading to the formation of 5-oxo-tiagabine; and 2) glucuronidation. The 5-oxo-tiagabine metabolite does not contribute to the pharmacologic activity of tiagabine.
Based on in vitro data, tiagabine is likely to be metabolized primarily by the 3A isoform subfamily of hepatic cytochrome P450 (CYP 3A), although contributions to the metabolism of tiagabine from CYP 1A2, CYP 2D6 or CYP 2C19 have not been excluded.
Tiagabine is likely metabolized primarily by the 3A isoform subfamily of hepatic cytochrome P450.
Route of Elimination: Approximately 2% of an oral dose of tiagabine is excreted unchanged, with 25% and 63% of the remaining dose excreted into the urine and feces, respectively, primarily as metabolites.
Half Life: 7-9 hours

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Biological Half-Life
7-9 hours
... The average elimination half-life for tiagabine in healthy subjects ranged from 7 to 9 hours. The elimination half-life decreased by 50 to 65% in hepatic enzyme-induced patients with epilepsy compared to uninduced patients with epilepsy.
Its half-life is about 8 hrs but is shortened by 2 to 3 hrs when coadministered with hepatic enzyme-inducing drugs such as phenobarbital, phenytoin, or carbamazepine.

Toxicity Summary
Though the exact mechanism by which Tiagabine exerts its effect on the human body is unknown, it does appear to operate as a selective GABA reuptake inhibitor.

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Hepatotoxicity
Limited data are available on the hepatotoxicity of tiagabine. In clinical trials, therapy with tiagabine was not associated with an increased frequency of serum aminotransferase elevations or liver toxicity. No individual case reports of liver injury from tiagabine have been published and its use has not been associated with hypersensitivity syndromes or autoimmunity. However, its overall use has been limited.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Monitor the infant for drowsiness, adequate weight gain, and developmental milestones, especially in younger, exclusively breastfed infants and when using combinations of anticonvulsant or psychotropic drugs. Because there is very limited published experience with tiagabine during breastfeeding, other agents may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
One mother breastfed her infant while taking tiagabine 24 mg and then 20 mg daily.
No adverse effects were reported in 10 newborns who were 4 to 23 days old who were breastfed during maternal intake of levetiracetam 1000 to 3000 mg daily. One mother was also taking tiagabine 30 mg daily, clobazam 45 mg daily and oxcarbazepine 600 mg daily.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
96%

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Interactions
/Concomitant administration of tiagabine with/ alcohol or central nervous system depression-producing medications may increase CNS depression.
Tiagabine clearance is increased by 60% in patients taking carbamazepine, phenobarbital, phenytoin, or primidone.
Tiagabine causes a slight decrease (about 10%) in steady-state valproate concentrations; in vitro studies have shown that valproate decreases the protein binding of tiagabine from 96.3 to 94.8, resulting in an increase of approximately 40% in the free tiagabine concentration; clinical relevance of this finding is unknown.
Co-administration of cimetidine (800 mg/day) to patients taking tiagabine chronically had no effect on tiagabine pharmacokinetics.
For more Interactions (Complete) data for TIAGABINE (13 total), please visit the HSDB record page.

:Cochrane Database Syst Rev. 2012 Dec 12;12:CD004694.

Tiagabine is a piperidinemonocarboxylic acid that is (R)-nipecotic acid in which the hydrogen attached to the nitrogen has been replaced by a 1,1-bis(3-methyl-2-thienyl)but-1-en-4-yl group. A GABA reuptake inhibitor, it is used (generally as the hydrochloride salt) for the treatment of epilepsy. It has a role as a GABA reuptake inhibitor and an anticonvulsant. It is a piperidinemonocarboxylic acid, a beta-amino acid, a member of thiophenes and a tertiary amino compound. It is functionally related to a (R)-nipecotic acid. It is a conjugate base of a tiagabine(1+).
Tiagabine is an anti-convulsive medication. It is also used in the treatment for panic disorder as are a few other anticonvulsants. Though the exact mechanism by which tiagabine exerts its effect on the human body is unknown, it does appear to operate as a selective GABA reuptake inhibitor.
Tiagabine is an Anti-epileptic Agent. The physiologic effect of tiagabine is by means of Decreased Central Nervous System Disorganized Electrical Activity.
Tiagabine is a unique anticonvulsant used largely as an adjunctive agent in therapy of partial seizures in adults or children. Therapy with tiagabine is not associated with serum aminotransferase elevations, and clinically apparent liver injury from tiagabine has not been reported and must be rare if it occurs at all.
Tiagabine is an anti-convulsive medication. It is also used in the treatment for panic disorder as are a few other anticonvulsants. Though the exact mechanism by which tiagabine exerts its effect on the human body is unknown, it does appear to operate as a selective GABA reuptake inhibitor.
A nipecotic acid derivative that acts as a GABA uptake inhibitor and anticonvulsant agent. It is used in the treatment of EPILEPSY, for refractory PARTIAL SEIZURES.
See also: Tiagabine Hydrochloride (has salt form); Tiagabine hydrochloride monohydrate (is active moiety of).

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Drug Indication
For the treatment of partial seizures
FDA Label

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Mechanism of Action
Though the exact mechanism by which Tiagabine exerts its effect on the human body is unknown, it does appear to operate as a selective GABA reuptake inhibitor.
Although the precise mechanism of action of tiagabine is unknown, the drug enhances inhibitory neurotransmission mediated by gamma-aminobutyric acid (GABA). Tiagabine increases the amount of GABA available in extracellular spaces of the globus pallidus, ventral pallidum, and substantia nigra, suggesting a GABA-mediated anticonvulsant mechanism of action (i.e., inhibition of neural impulse propagations that contribute to seizures). Tiagabine inhibits presynaptic neuronal and glial GABA reuptake, and increases the amount of GABA available for postsynaptic receptor binding. The drug does not stimulate GABA release, and does not have activity at other receptor binding and uptake sites at concentrations that inhibit the uptake of GABA. Tiagabine selectively blocks presynaptic GABA uptake by binding reversibly and saturably to recognition sites associated with GABA transporter protein in neuronal and glial membranes.
In vitro binding studies indicate that tiagabine does not inhibit substantially the uptake of dopamine, norepinephrine, serotonin, glutamate, or choline, and does not bind substantially to dopamine D1 or D2; cholinergic muscarinic; serotonergic type 1A, type 2, or type 3 (5HT1A, 5HT2, or 5HT3, respectively); alpha1- or alpha2-adrenergic; beta1- or beta2-adrenergic; histamine H2 or H3; adenosine A1 or A2; opiate mu or kappa1; glutamate N-methyl-d- aspartate (NMDA); or GABAA receptors. Also, tiagabine has little or no affinity for sodium or calcium channels. Tiagabine binds to histamine H1, serotonergic type 1B (5HT1B), benzodiazepine, and chloride channel receptors at concentrations 20-400 times those that inhibit the uptake of GABA.

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Therapeutic Uses
Tiagabine is indicated as an adjunct to other anticonvulsant medications in the treatment of partial seizures in adults and children 12 years of age and older. /Included in US product label/

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Drug Warnings
Although tiagabine reduces the frequency of seizures in patients with epilepsy, use of the drug has been associated with a paradoxical occurrence of seizures in patients without a history of epilepsy.
Post-marketing reports have shown that /tiagabine/ use has been associated with new onset seizures and status epilepticus in patients without epilepsy. Dose may be an important predisposing factor in the development of seizures, although seizures have been reported in patients taking daily doses of /tiagabine/ as low as 4 mg/day. In most cases, patients were using concomitant medications (antidepressants, antipsychotics, stimulants, narcotics) that are thought to lower the seizure threshold. Some seizures occurred near the time of a dose increase, even after periods of prior stable dosing.
The /tiagabine/ dosing recommendations in current labeling for treatment of epilepsy were based on use in patients with partial seizures 12 years of age and older, most of whom were taking enzyme-inducing antiepileptic drugs (AEDs; e.g., carbamazepine, phenytoin, primidone and phenobarbital) which lower plasma levels of /tiagabine/ by inducing its metabolism. Use of /tiagabine/ without enzyme-inducing antiepileptic drugs results in blood levels about twice those attained in the studies on which current dosing recommendations are based
Safety and effectiveness of /tiagabine/ have not been established for any indication other than as adjunctive therapy for partial seizures in adults and children 12 years and older.
For more Drug Warnings (Complete) data for TIAGABINE (19 total), please visit the HSDB record page.

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Pharmacodynamics
Tiagabine is used primarily as an anticonvulsant for the adjunctive treatment of epilepsy. 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.

C₂₀H₂₅NO₂S₂

375.55

375.132

115103-54-3

Tiagabine hydrochloride;145821-59-6;Tiagabine hydrochloride hydrate;145821-57-4

60648

Typically exists as solid at room temperature

1.208 g/cm3

568ºC at 760 mmHg

192oC dec.

297.3ºC

9.71E-14mmHg at 25°C

1.604

5.784

97.02

1

5

6

25

474

1

O=C([C@H]1CN(CC/C=C(C2=C(C)C=CS2)/C3=C(C)C=CS3)CCC1)O

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

(R)-1-(4,4-bis(3-methylthiophen-2-yl)but-3-en-1-yl)piperidine-3-carboxylic acid hydrochloride

NO-329; NNC05-0328; NO329; NNC-050328; NO 329; NNC-05-0328; NO-05-0328; trade name Gabitril

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。