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药品详细

Vigabatrin(氨己烯酸)

化学结构式图
中文名
氨己烯酸
英文名
Vigabatrin
分子式
C6H11NO2
化学名
4-aminohex-5-enoic acid
分子量
Average: 129.157
Monoisotopic: 129.078978601
CAS号
60643-86-9
ATC分类
N03A 未知
药物类型
small molecule
阶段
approved
商品名
同义名
基本介绍

An analogue of gamma-aminobutyric acid, vigabatrin is an irreversible inhibitor of 4-aminobutyrate transaminase, the enzyme responsible for the catabolism of gamma-aminobutyric acid. (From Martindale The Extra Pharmacopoeia, 31st ed). Off-label uses include treatment of cocaine dependence.

生产厂家
  • Lundbeck inc
封装厂家
参考
Synthesis Reference Not Available
General Reference
  1. Gram L, Larsson OM, Johnsen A, Schousboe A: Experimental studies of the influence of vigabatrin on the GABA system. Br J Clin Pharmacol. 1989;27 Suppl 1:13S-17S. Pubmed
  2. Browne TR: Pharmacokinetics of antiepileptic drugs. Neurology. 1998 Nov;51(5 Suppl 4):S2-7. Pubmed
  3. Lindberger M, Luhr O, Johannessen SI, Larsson S, Tomson T: Serum concentrations and effects of gabapentin and vigabatrin: observations from a dose titration study. Ther Drug Monit. 2003 Aug;25(4):457-62. Pubmed
  4. Zwanzger P, Baghai TC, Schuele C, Strohle A, Padberg F, Kathmann N, Schwarz M, Moller HJ, Rupprecht R: Vigabatrin decreases cholecystokinin-tetrapeptide (CCK-4) induced panic in healthy volunteers. Neuropsychopharmacology. 2001 Nov;25(5):699-703. Pubmed
  5. Tulloch JK, Carr RR, Ensom MH: A systematic review of the pharmacokinetics of antiepileptic drugs in neonates with refractory seizures. J Pediatr Pharmacol Ther. 2012 Jan;17(1):31-44. doi: 10.5863/1551-6776-17.1.31. Pubmed
  6. Clayton LM, Stern WM, Newman WD, Sander JW, Acheson J, Sisodiya SM: Evolution of visual field loss over ten years in individuals taking vigabatrin. Epilepsy Res. 2013 Mar 28. pii: S0920-1211(13)00074-0. doi: 10.1016/j.eplepsyres.2013.02.014. Pubmed
  7. Hawker DD, Silverman RB: Synthesis and evaluation of novel heteroaromatic substrates of GABA aminotransferase. Bioorg Med Chem. 2012 Oct 1;20(19):5763-73. doi: 10.1016/j.bmc.2012.08.009. Epub 2012 Aug 16. Pubmed
剂型
规格
化合物类型
Type small molecule
Classes
  • Amino Acids
Substructures
  • Amino Acids
  • Hydroxy Compounds
  • Alkanes and Alkenes
  • Acetates
  • Aliphatic and Aryl Amines
  • Carboxylic Acids and Derivatives
适应症
药理
Indication For use as an adjunct in treatment resistant epilepsy, refractory complex partial seizures, and secondary generalized seizures. It is also used as monotherapy in infantile spasms in West syndrome.
Pharmacodynamics Vigabatrin is an anticonvulsant chemically unrelated to other anticonvulsants. Vigabatrin prevents the catabolism of GABA by irreversibly inhibiting the enzyme GABA transaminase. It is an analog of GABA, but it is not a receptor agonist. However, vigabatrin is not a potent inhibitor of GABA-T with a Ki of 10 mM.
Mechanism of action Vigabatrin increases brain concentrations of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the CNS, by irreversibly inhibiting enzymes that catabolize GABA (gamma-aminobutyric acid transaminase, GABA-T). Duration of action is determined by rate of GABA-T re-synthesis. Vigabatrin may also work by suppressing repetitive neuronal firing through inhibition of voltage-sensitive sodium channels. Although administered as a racemic mixture, only the S(+) enantiomer is pharmacologically active.
Absorption Rapidly absorbed following oral administration, absorption is comparable between neonates, infants, and children. Cmax, 50 mg/kg dose, neonates= 14 mg/L; Tmax, 50 mg/kg dose, neonates = 2.1 hours; However, extent of absorption is higher and elimination half life is longer in neonates compared to children and infants. This is because neonates have reduced renal function compared to the aforementioned population groups. AUC, 50 mg/kg dose, neonates = 142.6 ± 44.0 mg/L/hr; Food may slightly decrease the rate (Cmax decreased by 33%, Tmax increased to 2 hours), but not the extent of absorption. Furthermore, vigabatrin does not cross the blood-brain-barrier well, thus high doses are needed.
Volume of distribution

1.1 L/kg
Protein binding Not protein bound
Metabolism
Almost no metabolic transformation. Does not induce the hepatic cytochrome P450 system.
Route of elimination Eliminated primarily through renal excretion as unchanged drugs (80%).
Half life Neonates, 50 mg/kg = 7.5 ± 2.1 hours (due to reduced renal function); Infants = 5.7 hours; Adults = 7.5 hours; Elderly = 12 - 13 hours
Clearance

Infants = 2.4 ± 0.8 L/h;
Children = 5.7 ± 2.5 L/h
Toxicity LD50, oral, rat: 3000 mg/kg; Visual field defects may occur following cumulative doses in excess of 2 kg.
Affected organisms
  • Humans and other mammals
Pathways Not Available
理化性质
Properties
State solid
Experimental Properties
Property Value Source
water solubility 55.1 mg/mL Not Available
logP -2.16 HENCZI,M ET AL. (1995)
Predicted Properties
Property Value Source
water solubility 9.66e+01 g/l ALOGPS
logP -2.6 ALOGPS
logP -2.1 ChemAxon
logS -0.13 ALOGPS
pKa (strongest acidic) 4.61 ChemAxon
pKa (strongest basic) 9.91 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 3 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 63.32 ChemAxon
rotatable bond count 4 ChemAxon
refractivity 34.29 ChemAxon
polarizability 13.64 ChemAxon
药物相互作用
Drug Interaction
Clonazepam Vigabatrin increases Cmax of clonazepam by 30% and decreases Tmax by 45%
Fosphenytoin Vigabatrin decreases the effect of hydantoin
Mefloquine Mefloquine may decrease the serum concentration of Vigabatrin. This may increase the risk of seizure in patients receiving Vigabatrin to prevent seizures. Consider alternate therapy or monitor for changes in Vigabatrin serum concentration, therapeutic or adverse effects if Mefloquin is initiated, discontinued or dose changed.
Methotrimeprazine Additive CNS depression may occur. Dose adjustments may be required if one agent is added to existing therapy with the other agent. Monitor for increased CNS depression during concomitant therapy.
Phenobarbital Vigabatrin reduces serum concentrations of phenobarbital by 8-16%.
Phenytoin Vigabatrin reduces plasma levels of phenytoin by 16-20% which may be due to induction of CYP2C. Consider dosage adjustment.
Sildenafil Increased anticonvulsant effects of vigabatrin due to pharmacodynamic synergism. Monitor for adverse effects during concomitant therapy.
Triprolidine The CNS depressants, Triprolidine and Vigabatrin, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
Valproic Acid Vigabatrin reduces serum concentrations of valproic acid by 8%.
食物相互作用
Not Available

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