substantial rise in epileptic threshold was found after systemic (intraperitoneal) injection of high doses (600 or 1200 mg/kg) of vigabatrin. Bilateral microinjection of vigabatrin (10 μg) into the anterior or posterior substantia nigra pars reticulata also improved the seizure threshold, but not as dramatically as systemic therapy. Local delivery to the subthalamic nucleus (STN) increases the epileptic threshold more dramatically than intranigra or systemic treatment of vigabatrin [1].

In Caco-2 and MDCK cells, vigabatrin at 30 mM reduced taurine uptake by 34% and 53%, respectively. Vigabatrin absorption in Caco-2 cells is concentration-dependent and saturable at neutral pH, with a Km value of 27 mM. In renal and intestinal cell culture models, vigabatrin decreases the absorption of taurine [2].

Absorption, Distribution and Excretion
Absorption after oral administration is essentially complete. The time to peak concentration (Tmax) is approximately 2.5 hours in infants (5 months to 2 years) and approximately 1 hour in other age groups. Within 72 hours after administration, approximately 95% of the drug is excreted in the urine, of which approximately 80% is the unchanged drug. Vegabatrin is widely distributed throughout the body, with a mean steady-state volume of distribution of 1.1 L/kg. The oral clearance is 2.4 L/h in infants (5 months to 2 years), 5.1 L/h in children (3 to 9 years), 5.8 L/h in adolescents (10 to 16 years), and 7 L/h in adults. Drug transporters in various tissues, including the intestines, kidneys, liver, and brain, are considered important mediators of drug absorption, distribution, metabolism, and excretion. This review summarizes the current research progress on transporters mediating the absorption, distribution, metabolism, and excretion of the antiepileptic drug vegabatrin. For oral medications, such as vegabatrin, intestinal absorption is a prerequisite for their bioavailability. Therefore, this article discusses in detail the transport proteins involved in the intestinal absorption of vegabatrin in vitro and in vivo, with a focus on the role of proton-coupled amino acid transporter 1 (PAT1) in the intestinal absorption of vegabatrin. Furthermore, this review summarizes the pharmacokinetic parameters of vegabatrin in different species and the drug-food and drug-drug interactions involving vegabatrin. This study aimed to determine the blood-brain barrier penetration and extracellular pharmacokinetics of the anticonvulsant vegabatrin (VGB; γ-vinyl-γ-aminobutyric acid) in the extracellular fluid and plasma of patients with severe traumatic brain injury (TBI), and to measure changes in the concentration of γ-aminobutyric acid (GABA) in the extracellular fluid. Ten patients with severe TBI received VGB treatment (0.5 g, enterally, every 12 hours). Each patient had a cerebral microdialysis catheter inserted; two patients had a second catheter inserted in different brain regions. Plasma samples were collected 0.5 hours before the first administration and at 2, 4, and 11.5 hours after administration. Brain microdialysis was initiated before the first administration of VGB and continued for at least three VGB administrations. The control group consisted of 7 patients with severe TBI who received microdialysis but not VGB. Following the first VGB administration, the maximum plasma VGB concentration (Cmax) was 31.7 (26.9–42.6) μmol/L (median and interquartile range of 8 patients), and the maximum VGB concentration in the brain microdialysis fluid was 2.41 (2.03–5.94) μmol/L (9 patients, 11 catheters), with no significant correlation between plasma and brain tissue concentrations. After three administrations, the median Cmax in the microdialysis fluid increased to 5.22 (4.24–7.14) μmol/L (8 patients, 10 catheters). VGB concentrations in the microdialysis fluid near the lesion were higher than those at distal lesions. In some patients, the concentration of GABA in the microdialysis fluid increased slightly after VGB treatment. Vegabatrine, administered enterally for the treatment of severe traumatic brain injury (TBI), can cross the blood-brain barrier into the extracellular fluid and accumulate there after repeated administrations. Pharmacokinetic studies have shown a delay in its absorption from the bloodstream. Vegabatrine is distributed into breast milk, but in small amounts. This study aimed to investigate the transport mechanism of vegabatrine in the rat intestine by establishing a population pharmacokinetic (PK) model of oral absorption. This PK model was used to investigate whether the absorption of vegabatrine is mediated by a carrier and whether proton-coupled amino acid transporter 1 (PAT1) is involved in the absorption process. Sprague Dawley rats were orally or intravenously injected with vegabatrine (0.3–300 mg/kg) with or without PAT1 ligands L-proline, L-tryptophan, or sarcosine. The pharmacokinetic characteristics of vegabatrine were described using a mechanistic nonlinear mixed-effects model, and the PAT1 ligand was evaluated as a covariate in pharmacokinetic parameters using a complete covariate modeling approach. Oral absorption of vegabatrine conformed to the Michaelis-Menten saturation absorption model. Using a Michaelis constant of 32.8 mM, the model estimated the maximum oral absorption rate (Vmax) to be 64.6 mmol/min, with bioavailability showing a dose-dependent effect, maximizing at 60.9%. Bioavailability ranged from 58.5% to 60.8% in the dose range of 0.3–30 mg/kg, but decreased to 46.8% at 300 mg/kg. The changes in oral vegabatrine pharmacokinetics following co-administration with the PAT1 ligand were attributed to a significant increase in the apparent Michaelis constant. Based on the mechanistic model, a high-capacity, low-affinity carrier is hypothesized to be involved in the intestinal absorption of vegabatrine. The increase in the Michaelis constant of vegabatrine after oral co-administration with the PAT1 ligand suggests that this carrier may be PAT1. For more complete data on the absorption, distribution, and excretion of vegabatrin (10 items in total), please visit the HSDB record page. Metabolism/Metabolites vegabatrin is hardly metabolized. Vegabatrin undergoes almost no metabolic transformation. It does not induce the hepatic cytochrome P450 system. Elimination route: Primarily excreted unchanged via the kidneys (80%). Half-life: Neonates, 50 mg/kg = 7.5 × 10⁻⁵ s⁻¹ 2.1 hours (due to impaired renal function); Infants = 5.7 hours; Adults = 7.5 hours; Elderly = 12-13 hours. The terminal half-life of vegabatrin is approximately 5.7 hours in infants (5 months-2 years), approximately 6.8 hours in children (3-9 years), approximately 9.5 hours in adolescents (10-16 years), and approximately 10.5 hours in adults.

Toxicity Summary
Identification and Uses: Vegabatrin is a structural analogue of gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the central nervous system (CNS). Vegabatrin is commercially available as a racemic mixture of two enantiomers; the S enantiomer is pharmacologically active, while the R enantiomer is inactive. Human Studies: Visual field defects, including permanent vision loss, have been reported in infants, children, and adults taking vegabatrin. Based on adult clinical studies, 30% or more of patients taking this drug may experience bilateral concentric visual field constriction, ranging in severity from mild to severe. Severe cases are characterized by visual field constriction to within 10 degrees of the fixation point, which can lead to disability. In some cases, vegabatrin can also damage the central retina and reduce visual acuity. Most cases of vegabatrin overdose present with coma, loss of consciousness, and/or drowsiness. Other less common symptoms include dizziness, psychosis, apnea or respiratory depression, bradycardia, agitation, irritability, confusion, headache, hypotension, behavioral abnormalities, increased seizures, status epilepticus, and speech disorders. These symptoms are generally relieved with supportive care. Animal studies: No carcinogenicity was observed in mice or rats fed up to 150 mg/kg/day for 18 months (mice) or up to 150 mg/kg/day for 2 years (rats). During organogenesis (days 7, 8, 9, 10, 11, or 12), daily intraperitoneal administration of vegabatrine (300 or 450 mg/kg) to mutant mouse strains resulted in increased rates of malformations (including cleft palate) at both doses. In rats, oral administration of vegabatrine (50, 100, or 150 mg/kg) during organogenesis led to decreased fetal weight and increased rates of fetal anatomical variations. Oral administration of vegabatrine (50, 100, or 150 mg/kg) from late pregnancy to weaning resulted in long-term neuropathological (hippocampal vacuolation) and neurobehavioral (convulsion) abnormalities in offspring. Oral administration of vegabatrine (50 to 200 mg/kg) to pregnant rabbits during organogenesis was associated with increased incidence of malformations (cleft palate) and embryo-fetal death; these findings are from two independent studies. In rats, no adverse effects on male or female fertility were observed at oral doses up to 150 mg/kg/day. Oral administration of vegabatrine (5, 15, or 50 mg/kg) to pups during neonatal and juvenile periods (days 4–65 after birth) resulted in neurobehavioral abnormalities (convulsions, neuromotor disorders, learning disabilities) and neuropathological abnormalities (brain vacuolation, reduced myelination, and retinal dysplasia). It is generally believed that the early postnatal period in rats corresponds to late pregnancy in humans in terms of brain development. In vitro (Ames test, CHO/HGPRT mammalian cell forward mutation assay, rat lymphocyte chromosome aberration assay) and in vivo (mouse bone marrow micronucleus assay) tests, vegabatrine was negative. Vegabatrine increases the concentration of GABA (an inhibitory neurotransmitter in the central nervous system) in the brain by irreversibly inhibiting the enzyme that breaks down γ-aminobutyric acid (GABA), γ-aminobutyrate transaminase (GABA-T). The duration of its effect depends on the rate of GABA-T resynthesis. Vegabatrine may also inhibit repetitive firing of neurons by inhibiting voltage-gated sodium channels. Although administered as a racemic mixture, only the S(+) enantiomer is pharmacologically active. Hepatotoxicity: In controlled clinical trials, the addition of vegabatrine to standard antiepileptic therapy has been reported to cause an immediate and significant decrease in serum enzyme levels, which can be reproduced simply by mixing vegabatrine with plasma. In some cases, significantly elevated serum ALT levels rapidly return to normal after treatment. Vegabatrine inhibits GABA transaminase and is therefore suspected of being an inhibitor of alanine aminotransferase and aspartate aminotransferase, which explains its abnormal effects on liver-related enzymes. In premarketing clinical trials, no cases of elevated serum enzymes or clinically significant liver injury were reported during treatment. However, following the widespread use of vegabatrine, there have been case reports of serious liver injury and hepatitis associated with its use. The injury occurred 3 to 10 months after initiation of vegabatrine and was primarily hepatocellular. One patient died rapidly from liver failure, and another patient's condition worsened after discontinuation of the drug, ultimately requiring immunosuppressive therapy with prednisone and azathioprine (Case 1). Therefore, vegabatrine use may lead to clinically significant liver injury, which can be severe, but this is relatively rare. Probability Score: D (Possibly a rare cause of clinically significant liver injury). Effects During Pregnancy and Lactation ◉ Overview of Use During Lactation: Limited information suggests that low concentrations of vegabatrine in breast milk are observed when mothers take up to 2000 mg daily. Vegabatrine is approved for use in infants one month and older, and concentrations in breast milk are significantly lower than the approved infant dose. No adverse effects are expected from vegabatrine in breastfed infants. ◉ Effects on Breastfed Infants: No published information found as of the revision date. ◉ Effects on Lactation and Breast Milk: No published information found as of the revision date. Protein Binding: Vegabatrine does not bind to plasma proteins. Toxicity Data: Oral LD50 in rats: 3000 mg/kg Interactions: Sabride may moderately increase the Cmax of clonazepam, thereby increasing the incidence of clonazepam-related adverse reactions.
Based on population pharmacokinetic models, concomitant administration of vegabatrin and rufetazone appears to result in a mild to moderate decrease in the mean steady-state plasma concentration of rufetazone (approximately). In adult patients, phenytoin sodium concentrations decreased by 14-15%, and in pediatric patients by approximately 30%. Although the clinical significance of this potential interaction remains to be determined, some clinicians recommend close monitoring of patients when starting or discontinuing either antiepileptic drug; and that rufetazone dosage adjustment should be considered if clinically necessary.
In controlled clinical studies, concomitant administration of phenytoin sodium and vigabatrin resulted in a moderate decrease in total plasma phenytoin sodium concentrations (mean decrease of 16-20%), likely due to CYP2C9 induction. In a pharmacokinetic study evaluating a potential interaction between vigabatrin and phenytoin sodium, the mean plasma phenytoin sodium concentration decreased by 23% at week 5 of concomitant administration. This decrease may be clinically insignificant and usually does not require dose adjustment of phenytoin sodium; however, dose adjustment of phenytoin sodium should be considered if clinically indicated. In a study of healthy subjects, concomitant administration of vegabatrine (1.5 g, twice daily) and clonazepam (0.5 mg) did not affect vegabatrine plasma concentrations; however, the mean peak plasma concentration of clonazepam increased by 30%, and the mean time to peak concentration decreased by 45%, which may increase the risk of clonazepam-related adverse reactions. In another study of healthy subjects, concomitant administration of vegabatrine did not appear to enhance the central nervous system effects of clonazepam. For more complete (7) data on drug interactions of vegabatrine, please visit the HSDB record page.

[1]. Vigabatrin for focal drug delivery in epilepsy: Bilateral microinfusion into the subthalamic nucleus is more effective than intranigral or systemic administration in a rat seizure model. Neurobiology of Disease (2012), 46(2), 362-376.

[2]. The anti-epileptic drug substance vigabatrin inhibits taurine transport in intestinal and renal cell culture models. Int J Pharm. 2014 Oct 1;473(1-2):395-7.

[3]. Gaily, Eija Vigabatrin monotherapy for infantile spasms. Expert Review of Neurotherapeutics (2012), 12(3), 275-286.

Therapeutic Uses
Anticonvulsant; Enzyme Inhibitor; GABA-like Drugs
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that indexes human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes a summary of the study protocol, including: disease or condition; intervention (e.g., the medical product, behavior, or procedure under investigation); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (for providing patient health information) and PubMed (for providing citations and abstracts of academic articles in the medical field). Vegabatrin is indexed in the database.
Sabrib is indicated as adjunctive therapy in adults and children aged 10 years and older with refractory complex partial epilepsy who have not responded well to multiple alternative therapies and whose potential benefit outweighs the risk of vision loss. Sabril is not indicated for first-line treatment of complex partial epilepsy. /US product label contains/
Sabril is indicated for use as monotherapy in infants aged 1 month to 2 years with spasms, where the potential benefits outweigh the risk of vision loss. /US product label contains/

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Drug Warnings
/Black Box Warning/ Warning: Permanent vision loss. Sabril can cause permanent bilateral concentric visual field narrowing, including tubular visual field, leading to disability. In some cases, sabril can also damage the central retina and may reduce visual acuity. Vision loss from sabril is unpredictable and may occur within weeks or less after starting treatment, or at any time after starting treatment, or even months or years later. Patients or caregivers often cannot detect symptoms of sabril-induced vision loss until it becomes severe. Mild vision loss, while often unnoticed by patients or caregivers, can still adversely affect function. The risk of vision loss increases with increasing dose and cumulative exposure, but there is currently no known dose or exposure that can completely eliminate the risk of vision loss. Visual acuity assessment is recommended at baseline (no later than 4 weeks after starting sabride), at least every 3 months during treatment, and approximately 3 to 6 months after discontinuation. Once sabride-induced visual loss is detected, it is irreversible. Even with frequent monitoring, some patients are expected to experience severe visual loss. If visual loss has been recorded, discontinuation should be considered after weighing the benefits and risks. There is a risk of new or worsening visual loss as long as sabride is used. Visual loss may worsen even after discontinuation of sabride. Due to the risk of visual loss, sabride should be discontinued in patients with treatment-resistant complex partial epilepsy if no significant clinical benefit is observed within 3 months of starting sabride; in patients with infantile spasms, it should be discontinued within 2–4 weeks of starting sabride, or as early as possible if treatment failure is evident. Patient response to sabride and the need for continued use should be reassessed periodically. Sabril should not be used in patients at high risk of developing or otherwise experiencing irreversible vision loss unless the benefits clearly outweigh the risks. Sabril should not be used concomitantly with other medications that may cause serious ocular adverse reactions, such as retinopathy or glaucoma, unless the benefits clearly outweigh the risks. Sabril should be used at the lowest possible dose and for the shortest possible duration, in line with clinical objectives. Due to the risk of permanent vision loss, Sabril is only available through a restricted program called the Vegabatrin Risk Assessment and Mitigation Strategy (REMS) program. Visual field defects, including permanent vision loss, have been reported in infants, children, and adults taking Vegabatrin. Based on adult clinical studies, 30% or more of patients taking this medication may experience bilateral concentric visual field narrowing, ranging in severity from mild to severe. Severe cases are characterized by visual field narrowing to within 10 degrees of the fixation point, which can lead to disability. In some cases, Vegabatrin can also damage the central retina and reduce visual acuity. Because assessing vision in infants and children can be challenging, the incidence and severity of vision loss in these patients are unclear; therefore, our understanding of this risk is primarily based on experience with adult users of this drug. The possibility that vegabatrin-induced vision loss is more common, more severe, or causes more serious functional consequences in infants and young children than in adults cannot be ruled out. The onset and progression of vegabatrin-induced vision loss are difficult to predict and may occur within weeks of starting treatment, or earlier, or even at any time after starting treatment, or even months or years later. Furthermore, vision loss may develop or worsen abruptly between two vision tests. Patients or caregivers are unlikely to recognize symptoms of vegabatrin-related vision loss before the vision impairment becomes severe. Even mild vision loss is often difficult for patients or caregivers to detect but can still adversely affect function. Once detected, vegabatrin-induced visual field defects are irreversible and will not improve even after discontinuation of the drug. Furthermore, vision may further deteriorate after discontinuation of the drug. The risk of vision loss increases with increasing vegabatrine dose and cumulative exposure; however, there is currently no evidence that any dose or drug exposure can completely prevent the risk of vision loss. Some studies suggest that smoking, age, and male sex may be risk factors for visual field defects. For patients with infantile spasms, vegabatrine treatment should be discontinued if no significant clinical benefit is observed within 2–4 weeks of starting treatment. If the prescribing physician, based on clinical judgment, observes significant signs of treatment failure within 2–4 weeks, vegabatrine treatment should be discontinued immediately. For more complete data on vegabatrine (25 total), please visit the HSDB records page.

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Pharmacodynamics
Vegabatrine is an antiepileptic drug with a chemical structure unrelated to other anticonvulsants. Vegabatrine prevents the metabolism of GABA by irreversibly inhibiting GABA transaminase (GABA-T). Since vegabatrin is an irreversible inhibitor of γ-aminobutyric acid transaminase (GABA-T), its duration of action is thought to depend on the rate of GABA-T resynthesis rather than the rate of drug elimination.

C6H11NO2

129.15704

129.078

68506-86-5

Vigabatrin hydrochloride;1391054-02-6

5665

White to off-white solid powder

1.1±0.1 g/cm3

277.7±28.0 °C at 760 mmHg

171-176C
209 °C

121.7±24.0 °C

0.0±1.2 mmHg at 25°C

1.483

-0.1

2

3

4

9

112

0

PJDFLNIOAUIZSL-UHFFFAOYSA-N

InChI=1S/C6H11NO2/c1-2-5(7)3-4-6(8)9/h2,5H,1,3-4,7H2,(H,8,9)

4-aminohex-5-enoic acid

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)

H2O : ~50 mg/mL (~387.12 mM)

Solubility in Formulation 1: 100 mg/mL (774.23 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)