抗癫痫药物非氨酯 (W-554) 用于治疗癫痫。在成人中，它用于治疗伴有或不伴有全身性癫痫发作的部分性癫痫发作，在儿童中，它用于治疗与 Lennox-Gastaut 综合征相关的部分性和全身性癫痫发作。然而，由于潜在致命的再生障碍性贫血和/或肝衰竭的风险增加，药物在严重难治性癫痫中的使用受到限制[1]。非拉氨酯 (W-554) 被认为具有独特的双重作用机制，可作为 NMDA 受体阻滞剂和 GABAA 受体（特别是含有 NR2B 亚基的异构体）的正调节剂。尽管非氨酯在药理学上明显抑制 NMDA 受体，但关于 NMDA 受体阻断作为人类癫痫治疗方法的适用性仍存在争议。因此，目前尚不清楚非氨酯对 NMDA 受体的影响对其治疗癫痫的能力有多重要 [2]。

Absorption, Distribution and Excretion
>90%
756±82 mL/kg
26 +/- 3 mL/hr/kg [single 1200 mg dose]
30 +/- 8 mL/hr/kg [multiple daily doses of 3600 mg]
/Absorption is/ complete (>90%). Absorption is unaffected by food, and both tablet and suspension dosage forms exhibit similar kinetics.
Felbamate enters the central nervous system (CNS), with a brain/plasma coefficient of approximately 0.9. The apparent volume of distribution (Vol D) ranged from 0.73 to 0.85 L per kg of body weight (L/kg) in single and multiple dose studies.
/Protein binding of felbamate is/ low (20-36%).
Clearance after a single 1200 mg dose is 26+/- 3 mL/hr/kg, and after multiple daily doses og 3600 mg is 30 +/- 8 mL/hr/kg. ... Felbamate Cmax and AUC are proportionate to dose after single and multiple doses over a range of 100-800 mg single doses and 1200-3600 mg daily doses. Cmin (trough) blood levels are also dose proportionate. ... Felbamate gave dose proportional steady-state peak plasma concentrations in children age 4-12 over a range of 15, 30, and 45 mg/kg/day with peak concentrations of 17, 32, and 49 ug/mL.
For more Absorption, Distribution and Excretion (Complete) data for 2-PHENYL-1,3-PROPANEDIOL DICARBAMATE (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Hepatic
/Biotransformation is/ hepatic, probably by the cytochrome P-450 system; primarily by hydroxylation and conjugation to metabolites that are neither pharmacologically active nor neurotoxic.
About 40-50% of absorbed dose appears in unchanged in urine, an additional 40% is present as unidentified metabolites and conjugates. About 15% is present parahydroxyfelbamate, 2-hydroxyfelbamate, and felbamate monocarbamate, none of which have significant anticonvulsant activity.
Felbamate (FBM; 2-phenyl-1,3-propanediol dicarbamate) is an approved antiepileptic drug shown to be effective in a variety of seizure disorders refractory to other treatments. However, its use has been restricted because of association with occurrence of rare cases of aplastic anemia and hepatic failure. Since it was shown that FBM metabolism requires glutathione (GSH), we used two experimental protocols to determine if the effects of specific metabolites were sensitive to redox pathways. FBM and its metabolite W873 (2-phenyl-1,3-propanediol monocarbamate), at 0.1 mg/mL, induced increased apoptosis of bone marrow cells from B10.AKM mice as compared with B10.BR mice. Study of the effects of the drug on human promonocytic cell line U937 cells showed that FBM and the metabolite W2986 [2-(4-hydroxyphenyl)-1,3 propanediol dicarbamate], at higher concentrations (0.5 mg/mL), induced apoptosis in this cell line. We also observed that while FBM and its metabolites induced increased apoptosis of B cells with reduced intracellular GSH levels, addition of exogenous GSH decreased apoptosis induced by W873 but did not significantly affect apoptosis induced by FBM or W2986. /The authors/ results suggest that, at concentrations used during the present investigations, FBM metabolites induce apoptosis via redox-sensitive and redox-independent pathways.
Antiepileptic therapy with a broad spectrum drug felbamate (FBM) has been limited due to reports of hepatotoxicity and aplastic anemia associated with its use. It was proposed that a bioactivation of FBM leading to formation of alpha,beta-unsaturated aldehyde, atropaldehyde (ATPAL) could be responsible for toxicities associated with the parent drug. Other members of this class of compounds, acrolein and 4-hydroxynonenal (HNE), are known for their reactivity and toxicity. It has been proposed that the bioactivation of FBM to ATPAL proceeds though a more stable cyclized product, 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one (CCMF) whose formation has been shown recently. Aldehyde dehydrogenase (ALDH) and glutathione transferase (GST) are detoxifying enzymes and targets for reactive aldehydes. This study examined effects of ATPAL and its precursor, CCMF on ALDH, GST and cell viability in liver, the target tissue for its metabolism and toxicity. A known toxin, HNE, which is also a substrate for ALDH and GST, was used for comparison. Interspecies difference in metabolism of FBM is well documented, therefore, human tissue was deemed most relevant and used for these studies. ATPAL inhibited ALDH and GST activities and led to a loss of hepatocyte viability. Several fold greater concentrations of CCMF were necessary to demonstrate a similar degree of ALDH inhibition or cytotoxicity as observed with ATPAL. This is consistent with CCMF requiring prior conversion to the more proximate toxin, ATPAL. GSH was shown to protect against ALDH inhibition by ATPAL. In this context, ALDH and GST are detoxifying pathways and their inhibition would lead to an accumulation of reactive species from FBM metabolism and/or metabolism of other endogenous or exogenous compounds and predisposing to or causing toxicity. Therefore, mechanisms of reactive aldehydes toxicity could include direct interaction with critical cellular macromolecules or indirect interference with cellular detoxification mechanisms.
Hepatic
Half Life: 20-23 hours

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Biological Half-Life
20-23 hours
Elimination /half-life is/ 13 to 23 hours.

Toxicity Summary
The mechanism by which felbamate exerts its anticonvulsant activity is unknown, but in animal test systems designed to detect anticonvulsant activity, felbamate has properties in common with other marketed anticonvulsants. In vitro receptor binding studies suggest that felbamate may be an antagonist at the strychnine-insensitive glycine-recognition site of the N-methyl-D-aspartate (NMDA) receptor-ionophore complex. Antagonism of the NMDA receptor glycine binding site may block the effects of the excitatory amino acids and suppress seizure activity. Animal studies indicate that felbamate may increase the seizure threshold and may decrease seizure spread. It is also indicated that felbamate has weak inhibitory effects on GABA-receptor binding, benzodiazepine receptor binding.

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Hepatotoxicity
Prospective studies suggest that chronic felbamate therapy is not accompanied by significant elevations in serum aminotransferase levels. Nevertheless, clinically apparent hepatotoxicity from felbamate is well described, although uncommon, estimated to occur in 1 in 18,500 to 25,000 exposures, often with severe outcome. The onset of injury is 1 to 6 months after starting therapy and the pattern of enzyme elevations is typically hepatocellular. More than a dozen instances of acute liver failure and death were attributed to felbamate before severe restrictions were placed upon its use. Felbamate has not been associated with anticonvulsant hypersensitivity syndrome and is a potential alternative for persons who have developed that syndrome from other anticonvulsants.
Likelihood score: B (highly likely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because no information is available on the use of felbamate during breastfeeding, and because it can cause potentially fatal hematologic and hepatic toxicities, authors of authoritative reviews recommend that breastfeeding not be undertaken during maternal felbamate therapy until more safety data are available.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
20-36%

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Toxicity Data
LD50: 5000 mg/kg (Oral, Rat) (A308)

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Interactions
Enzyme induction by phenytoin may lead to decreased felbamate plasma concentrations during concurrent use; increased felbamate plasma concentrations may occur when phenytoin dosage is reduced or phenytoin is discontinued; since both felbamate and phenytoin are hydroxylated by the cytochrome P-450 system, possible competitive inhibition of phenytoin metabolism may result in phenytoin plasma concentrations being increased by 20 to 40%, leading to increased adverse effects; ... plasma concentrations of phenytoin should be monitored ...
Felbamate may increase phenobarbital plasma concentrations, leading to increased adverse effects; phenobarbital dosage should be reduced by 20 to 33% when felbamate therapy is initiated, and plasma phenobarbital concentrations should be monitored ...
Felbamate may increase plasma concentrations of N-desmethylmethsuximide, an active metabolite of methsuximide, leading to increased adverse effects; methsuximide dosage should be reduced by 20 to 33% when felbamate therapy is initiated ...
Enzyme induction by carbamazepine may lead to decreased felbamate plasma concentrations; increased felbamate plasma concentrations may occur when carbamazepine dosage is reduced or carbamazepine is discontinued; concurrent use may also decrease carbamazepine plasma concentrations by about 20 to 30% and may increase the plasma concentrations of carbamazepine-10,11-epoxide, an active metabolite of carbamazepine, by about 60%, leading to an increase in adverse effects; carbamazepine dosage should be reduced by 20 to 33% when felbamate therapy is initiated, and plasma concentrations of carbamazepine should be monitored...
For more Interactions (Complete) data for 2-PHENYL-1,3-PROPANEDIOL DICARBAMATE (7 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral >5 g/kg
LD50 Rat ip 1625 mg/kg
LD50 Mouse oral >5 g/kg
LD50 Mouse ip 659 mg/kg

[1]. Use-dependent inhibition of the N-methyl-D-aspartate currents by felbamate: a gating modifier with selective binding to the desensitized channels. Mol Pharmacol. 2004 Feb;65(2):370-80.

[2]. Felbamate block of recombinant N-methyl-D-aspartate receptors: selectivity for the NR2B subunit. Epilepsy Res. 2000 Mar;39(1):47-55.

Therapeutic Uses
Felbamate is indicated as monotherapy or as an adjunct to other anticonvulsants for the treatment of partial seizures with or without generalization in adults with severe epilepsy that has not responded to other treatment. /Included in US product labe/
Felbamate is indicated as adjunctive therapy in the treatment of partial and generalized seizures associated with Lennox-Gastaut syndrome in children who have not responded to other treatment. /Included in US product label/

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Drug Warnings
Because use of felbamate has been associated with marked increases in the incidences of aplastic anemia and acute hepatic failure, the manufacturer (Carter-Wallace) in conjunction with FDA warns that the drug should only be initiated or continued in the management of seizures in patients for whom, in the clinician's judgment, the seizure disorder is refractory to alternative safer therapy and is so severe that the benefits of felbamate therapy are believed to outweigh the possible risk of aplastic anemia or acute hepatic failure. For patients already receiving the drug, the likelihood that abrupt withdrawal would pose an even greater risk than that of possible felbamate-associated aplastic anemia or acute hepatic failure also should be considered in the decision to discontinue therapy with the drug. Decisions about the potential benefits and risks of felbamate therapy generally should be made in consultation with appropriate hematologic and hepatic disease experts.
At least 21 reported cases (20 of which occurred in the US) of aplastic anemia have developed in association with felbamate therapy. The rate of aplastic anemia cases currently reported with the drug appears to be at least 40-100 times higher than the expected rate of 2-5 cases per million untreated individuals per year. However, because the onset of felbamate-induced aplastic anemia typically is delayed for weeks to months after initiation of the drug and a substantial fraction of patients had felbamate therapy withdrawn for other reasons prior to this period, the absolute rate of this anemia associated with felbamate probably is higher than the currently reported rate of 1 case per 5000 patients per year. Based on this probability, the manufacturer estimates that the actual risk of aplastic anemia associated with felbamate therapy may be as high as 1 case per 2000 patients (500 cases per million patients) per year or more among those who remain on the drug for longer than a few weeks. While postmarketing surveillance usually captures only a fraction of incident cases, the syndrome is still relatively rare, and no cases were observed during premarket testing in which more than 1600 patients received felbamate therapy. All reports of aplastic anemia associated with felbamate therapy to date have occurred in patients receiving the drug for at least 5 weeks.
Of the 21 patients who developed aplastic anemia while receiving felbamate therapy, 5 (all from the US) have died. While current experience and data are too limited to estimate reliably the fatality rate associated with felbamate-induced aplastic anemia, the estimated case fatality rate for untreated individuals with aplastic anemia from any cause ranges from 20-30%. However, historical fatality rates as high as 70% have been reported for aplastic anemia, and the risk of death secondary to this anemia generally varies with severity and etiology. Although most reported cases have been in white females, risk factors for the development of aplastic anemia in patients receiving felbamate therapy have not been identified. Whether age (range for cases to date: 12-68 years old), gender, or race of the patient, duration of exposure to the drug, dosage, or concomitant use of other anticonvulsant agents or drugs affects the incidence of aplastic anemia in patients receiving felbamate remains to be established. Therefore, the manufacturer recommends that felbamate therapy be discontinued in any patient receiving the drug and alternative therapy initiated as necessary, unless in the clinician's judgment continued felbamate therapy outweighs the risk for aplastic anemia.
Of the 10 patients who developed acute hepatic failure while receiving felbamate therapy, 4 have died, and 1 has received a liver transplant. Whether preexisting hepatic impairment increases the risk of fulminant hepatic failure is unknown; however, the manufacturer recommends that all patients be evaluated for evidence of hepatic impairment prior to initiation of felbamate therapy, and use of the drug is not recommended in patients with preexisting hepatic abnormalities. Other risk factors for the development of acute hepatic failure in patients receiving felbamate have not been identified. Whether age (range for cases to date: 5-78 years old), gender, or race of the patient, duration of exposure to the drug, dosage, or concomitant use of other anticonvulsant agents or drugs affects the incidence of acute hepatic failure in patients receiving felbamate remains to be established.
For more Drug Warnings (Complete) data for 2-PHENYL-1,3-PROPANEDIOL DICARBAMATE (29 total), please visit the HSDB record page.

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Pharmacodynamics
Felbamate is an antiepileptic indicated as monotherapy or as an adjunct to other anticonvulsants for the treatment of partial seizures resulting from epilepsy. Receptor-binding studies in vitro indicate that felbamate has weak inhibitory effects on GABA-receptor binding, benzodiazepine receptor binding, and is devoid of activity at the MK-801 receptor binding site of the NMDA receptor-ionophore complex. However, felbamate does interact as an antagonist at the strychnine-insensitive glycine recognition site of the NMDA receptor-ionophore complex.

C11H14N2O4

238.24

238.095

25451-15-4

Felbamate-d4;106817-52-1;Felbamate hydrate;1177501-39-1;Felbamate-d5;1191888-51-3

3331

White to off-white solid powder

1.3±0.1 g/cm3

511.9±50.0 °C at 760 mmHg

148-1500C

288.4±26.4 °C

0.0±1.3 mmHg at 25°C

1.559

1.2

104.64

2

4

7

17

246

0

WKGXYQFOCVYPAC-UHFFFAOYSA-N

InChI=1S/C11H14N2O4/c12-10(14)16-6-9(7-17-11(13)15)8-4-2-1-3-5-8/h1-5,9H,6-7H2,(H2,12,14)(H2,13,15)

2-phenylpropane-1,3-diyl dicarbamate

ADD-03055; W-554; W 554; W554; ADD03055; ADD 03055; Felbamate; brand name: Felbatol; Felbamyl; Taloxa.

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)

配方 1 中的溶解度: ≥ 2.75 mg/mL (11.54 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 27.5 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.75 mg/mL (11.54 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 27.5mg/mL澄清的DMSO储备液加入到900μL 20％SBE-β-CD生理盐水中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.75 mg/mL (11.54 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 27.5 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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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。