Felbamate targets N-methyl-D-aspartate (NMDA) receptors [1]
Felbamate targets recombinant NMDA receptors composed of NR1/NR2A, NR1/NR2B, NR1/NR2C, NR1/NR2D subunits (IC50 for NR1/NR2B: ~30 μM; IC50 for NR1/NR2A, NR1/NR2C, NR1/NR2D: >100 μM) [2]

The anti-epileptic medication felbamate (W-554) is used to treat epilepsy. In adults, it is used to treat partial seizures with or without generalized seizures, and in children, it is used to treat partial and generalized seizures linked to Lennox-Gastaut syndrome. However, the use of medications in severe refractory epilepsy is restricted due to the increased risk of potentially fatal aplastic anemia and/or liver failure [1]. Felabamate (W-554) is thought to have a distinct dual mechanism of action, functioning as an NMDA receptor blocker and a positive modulator of GABAA receptors (particularly isoforms containing the NR2B subunit). Though it is evident that felbamate pharmacologically inhibits NMDA receptors, there has been debate regarding the applicability of NMDA receptor blockade as a treatment approach for epilepsy in humans. Therefore, it's unclear how important felbamate's impact on NMDA receptors is for its ability to treat epilepsy [2].

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1. Felbamate inhibits NMDA-evoked currents in a concentration-dependent manner (effective concentrations ranging from 10 μM to 1 mM) in cultured rat cortical neurons. The inhibition is use-dependent, with greater suppression of currents evoked by high-frequency or prolonged agonist application, indicating preferential binding to desensitized NMDA channels [1]
2. The inhibitory effect of Felbamate on NMDA currents is voltage-independent, and it does not alter the agonist affinity of NMDA receptors or the reversal potential of NMDA currents [1]
3. On recombinant NMDA receptors expressed in HEK293 cells, Felbamate shows selective inhibition for NR1/NR2B subunit combination, with an IC50 of ~30 μM. It exhibits weak or no inhibition on NR1/NR2A, NR1/NR2C, or NR1/NR2D combinations at concentrations up to 100 μM [2]
4. The inhibition of NR1/NR2B receptors by Felbamate is partially reversible upon washout, and the degree of inhibition increases with the duration of agonist exposure (desensitization-dependent) [2]

1. NMDA receptor current recording in cortical neurons: Cultured rat cortical neurons are prepared, and whole-cell patch-clamp recordings are performed. NMDA is applied as the agonist at a specific concentration to evoke inward currents. Felbamate is added to the extracellular solution at concentrations of 10 μM, 30 μM, 100 μM, 300 μM, and 1 mM sequentially. Currents are recorded before and after drug application, with high-frequency agonist pulses (500 ms duration, 0.5 Hz frequency) used to induce channel desensitization. The amplitude of NMDA currents is measured to calculate the inhibition rate [1]
2. Recombinant NMDA receptor current recording: HEK293 cells are transfected with cDNA encoding NMDA receptor subunits (NR1 plus NR2A, NR2B, NR2C, or NR2D). Whole-cell patch-clamp recordings are conducted at a holding potential of -60 mV. NMDA (100 μM) plus glycine (10 μM) are used to evoke currents. Felbamate is applied at concentrations ranging from 1 μM to 300 μM, and currents are recorded continuously. Dose-response curves are generated to determine IC50 values for each subunit combination [2]

1. Rat cortical neuron culture and patch-clamp assay: Cortical tissues are dissected from embryonic rats, dissociated into single cells, and cultured in appropriate medium for 10-14 days. Cells with neuronal morphology are selected for whole-cell patch-clamp. The intracellular solution contains specific electrolytes, and the extracellular solution includes NMDA, glycine, and other necessary components. Felbamate is diluted in the extracellular solution to the desired concentrations. After establishing the whole-cell configuration, baseline NMDA currents are recorded, followed by application of Felbamate for 5-10 minutes. Current amplitude changes are analyzed to evaluate the inhibitory effect [1]
2. HEK293 cell transfection and NMDA receptor assay: HEK293 cells are cultured in standard medium and transfected with NMDA receptor subunit cDNAs using a transfection reagent. Transfected cells are incubated for 24-48 hours to allow receptor expression. Whole-cell patch-clamp is performed on transfected cells, with NMDA and glycine applied to activate receptors. Felbamate is added to the bath solution at various concentrations, and currents are recorded. The reversibility of inhibition is tested by washing out the drug with fresh extracellular solution [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 3600 mg dose] Absorption/Complete (>90%). Food does not affect absorption; pharmacokinetics of tablets and suspensions are similar. Felbamate enters the central nervous system (CNS), with a brain/plasma coefficient of approximately 0.9. Apparent volume of distribution (Vol D) ranged from 0.73 to 0.85 L/kg body weight (L/kg) in single and multiple-dose studies. Felbamate has low protein binding (20-36%). Clearance after a single 1200 mg dose is 26±3 mL/hr/kg, and clearance after multiple daily doses (3600 mg per dose) is 30±8 mL/hr/kg. ...Within the single-dose range of 100-800 mg and the daily dose range of 1200-3600 mg, the Cmax and AUC of felbamate were dose-dependent. Cmin (trough concentration) plasma concentrations were also dose-dependent. ...In children aged 4-12 years, steady-state peak plasma concentrations of felbamate were dose-dependent at doses of 15, 30, and 45 mg/kg/day, with peak concentrations of 17, 32, and 49 μg/mL, respectively.
For more complete data on the absorption, distribution, and excretion of 2-phenyl-1,3-propanediol dicarboxylate esters (8 in total), please visit the HSDB record page.

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Metabolism/Metabolites
Hepatic
/Biotransformation/Primarily occurs in the liver, possibly via the cytochrome P-450 system; mainly through hydroxylation and conjugation to generate metabolites that are neither pharmacologically active nor neurotoxic. Approximately 40-50% of the absorbed dose is excreted unchanged in the urine, with another 40% present as unidentified metabolites and conjugates. About 15% of the composition consists of p-hydroxyfelamine, 2-hydroxyfelamine, and felamine monocarbamate, none of which exhibit significant anticonvulsant activity. Felamine (FBM; 2-phenyl-1,3-propanediol dicarbamate) is an approved antiepileptic drug that has been shown to be effective for seizures unresponsive to various other therapies. However, its use is limited due to its association with rare cases of aplastic anemia and liver failure. Given that the metabolism of FBM has been shown to require glutathione (GSH), we employed two experimental protocols to determine whether the action of specific metabolites is sensitive to redox pathways. A concentration of 0.1 mg/mL of FBM and its metabolite W873 (2-phenyl-1,3-propanediol monocarbamate) induced increased apoptosis in bone marrow cells of B10.AKM mice, but not in B10.BR mice. Studies on the human premonocyte cell line U937 showed that high concentrations (0.5 mg/mL) of FBM and its metabolite W2986 [2-(4-hydroxyphenyl)-1,3-propanediol dicarbamate] induced apoptosis in this cell line. We also observed that FBM and its metabolites increased apoptosis in B cells with decreased intracellular GSH levels, while the addition of exogenous GSH reduced W873-induced apoptosis, but had no significant effect on FBM- or W2986-induced apoptosis. These results indicate that at the concentrations used in this study, FBM metabolites can induce apoptosis through both redox-sensitive and redox-independent pathways.
The use of the broad-spectrum antiepileptic drug felbamate (FBM) in antiepileptic treatment has been limited due to reports of hepatotoxicity and aplastic anemia. Some studies suggest that the bioactivation of FBM to the α,β-unsaturated aldehyde atropinealdehyde (ATPAL) may be the cause of the parent drug's toxicity. Other members of this class of compounds, such as acrolein and 4-hydroxynonenal (HNE), are also known for their reactivity and toxicity. Research has proposed that the bioactivation of FBM to ATPAL occurs via a more stable cyclization product, 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one (CCMF), the formation of which has recently been confirmed. Aldehyde dehydrogenase (ALDH) and glutathione transferase (GST) are detoxification enzymes and targets of active aldehydes. This study investigated the effects of ATPAL and its precursor CCMF on ALDH, GST, and cell viability in the liver (a target tissue for ATPAL metabolism and toxicity). Meanwhile, this study also used a known toxin, HNE, as a control; HNE is also a substrate for ALDH and GST. Interspecies differences in FBM metabolism are well documented, therefore, this study considers human tissue to be most relevant. ATPAL inhibits ALDH and GST activity, leading to decreased hepatocyte viability. CCMF concentrations need to be several times higher to achieve similar levels of ALDH inhibition or cytotoxicity as ATPAL. This is consistent with the fact that CCMF needs to be converted to the more direct toxin ATPAL first. GSH has been shown to counteract the inhibitory effect of ATPAL on ALDH. In this context, ALDH and GST are detoxification pathways; inhibiting them leads to the accumulation of reactive substances produced by FBM metabolism and/or other endogenous or exogenous compound metabolism, thereby inducing or causing toxicity. Therefore, the toxic mechanisms of reactive aldehydes may include direct interactions with key cellular macromolecules or indirect interference with cellular detoxification mechanisms.
Liver
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 of action of felbamate in exerting its anticonvulsant effect is not fully understood, but in animal testing systems used to detect its anticonvulsant activity, felbamate shares common characteristics with other marketed anticonvulsant drugs. In vitro Receptor binding studies suggest that felbamate may be an antagonist of the glycine recognition site in the N-methyl-D-aspartate (NMDA) receptor-ionopeptide complex, which is insensitive to strychnine. Antagonism of the NMDA receptor glycine binding site may block the action of excitatory amino acids and inhibit seizures. Animal studies have shown that felbamate may increase the seizure threshold and reduce seizure spread. Studies have also shown that felbamate has a weak inhibitory effect on GABA receptor binding and benzodiazepine receptor binding. Hepatotoxicity
Prospective studies have shown that long-term use of felbamate does not lead to a significant increase in serum transaminase levels. However, while clinical hepatotoxicity caused by felbamate is uncommon (estimated incidence of 1/18,500 to 1/25,000), it has been described in detail and often leads to serious consequences. Liver injury typically appears 1 to 6 months after the start of treatment, with the pattern of enzyme elevation usually hepatocellular. Before its strict restriction, there were more than a dozen cases of acute liver failure and death attributed to felbamate. Felbamate is not associated with anticonvulsant hypersensitivity syndrome and may be an alternative for patients who develop this syndrome due to other anticonvulsants.
Probability Score: B (Very likely to cause clinically significant liver injury).

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Pregnancy and Lactation Effects
◉ Overview of Use During Lactation
Because there is currently no information regarding the use of felbamate during lactation, and given the potential for fatal hematologic and hepatotoxicity, the authors of the authoritative review recommend that mothers should not breastfeed while receiving felbamate treatment until more safety data are available.
◉ Impact on breastfed infants
No published information found as of the revision date.
◉ Impact on breastfeeding and breast milk
No published information found as of the revision date.

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Protein Binding Rate
20-36%Toxicity Data
LD50: 5000 mg/kg (oral, rat) (A308)Interactions
The enzymatic induction of phenytoin sodium may lead to a decrease in plasma concentrations of felbamate when used concurrently; plasma concentrations of felbamate may increase when the dose of phenytoin sodium is reduced or discontinued; since both felbamate and phenytoin sodium are hydroxylated via the cytochrome P-450 system, competitive inhibition of phenytoin sodium metabolism may lead to a 20% to 40% increase in plasma concentrations of phenytoin sodium, thereby increasing adverse reactions;…plasma concentrations of phenytoin sodium should be monitored…
Felbamate may increase plasma concentrations of phenobarbital, thereby increasing adverse reactions; when starting treatment with felbamate, the dose of phenobarbital should be reduced by 20%.
Up to 33%, and plasma phenobarbital concentrations should be monitored…
Felbamate may increase plasma concentrations of N-desmethylmethosuximide (the active metabolite of methosuximide), leading to increased adverse reactions; when starting treatment with fenbamate, the dose of methosuximide should be reduced by 20% to 33%…
Enzyme induction of carbamazepine may cause a decrease in fenbamate plasma concentrations; when reducing the dose of carbamazepine or discontinuing carbamazepine, fenbamate plasma concentrations may increase; concomitant use of fenbamate may also decrease carbamazepine plasma concentrations by approximately 20% to 30%, and may increase the plasma concentration of carbamazepine's active metabolite, carbamazepine-10,11-epoxide, by approximately 60%, leading to increased adverse reactions; when starting treatment with fenbamate, the dose of carbamazepine should be reduced by 20% to 33%, and plasma carbamazepine concentrations should be monitored…
Regarding 2-phenyl-1,3-propanediol dicarboxylate (total 7… For more complete data on interactions between species, please visit the HSDB record page.

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Non-human toxicity values
Rats oral LD50 >5 g/kg
Rats intraperitoneal LD50 1625 mg/kg
Mice oral LD50 >5 g/kg
Mice intraperitoneal LD50 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
Felamine may be used as monotherapy or in combination with other antiepileptic drugs for the treatment of partial seizures (with or without generalized seizures) in adult patients with severe epilepsy who have failed other treatments. /US Product Label Includes/ Felamine may be used as adjunctive therapy for the treatment of partial and generalized seizures in children with Lennox-Gastaut syndrome who have failed other treatments. /US Product Label Includes/

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Drug Warnings Due to the significantly increased incidence of aplastic anemia and acute liver failure associated with the use of fenamine, the manufacturer (Carter-Wallace) and the US Food and Drug Administration (FDA) jointly issue a warning: This drug should only be used in patients whose seizures are deemed by a clinician to be unresponsive to other, safer therapies and whose condition is so severe that the benefit of fenamine treatment is considered to outweigh the potential risks of aplastic anemia or acute liver failure. For patients already receiving this medication, the risks of abrupt discontinuation should be considered when deciding to discontinue treatment, as they may be even greater than the risks of felbamate-related aplastic anemia or acute liver failure. Decisions regarding the potential benefits and risks of felbamate treatment should generally be made in consultation with appropriate hematologists and hepatologists. At least 21 cases of aplastic anemia (20 of which occurred in the United States) have been reported as being associated with felbamate treatment. The currently reported incidence of drug-related aplastic anemia appears to be at least 40-100 times higher than the expected incidence (2-5 cases per million untreated patients per year). However, because felbamate-induced aplastic anemia typically develops weeks to months after starting treatment, and a significant proportion of patients discontinue felbamate treatment for other reasons before this, the absolute incidence of this type of anemia associated with felbamate may be higher than the currently reported 1 case per 5,000 patients per year. Based on this probability, the manufacturer estimates that the actual risk of aplastic anemia associated with non-aminobutyrate treatment may be as high as 1 in 2,000 patients per year (500 per million patients), with a higher risk in patients treated for more than several weeks. Although post-marketing surveillance typically detects only a subset of cases, the syndrome remains relatively rare; no cases were observed in pre-market testing of over 1,600 patients treated with non-aminobutyrate. To date, all reports of aplastic anemia associated with non-aminobutyrate treatment have occurred in patients treated with the drug for at least 5 weeks. Of the 21 patients who developed aplastic anemia during non-aminobutyrate treatment, 5 (all from the United States) died. While current experience and data are insufficient to reliably estimate the mortality rate of non-aminobutyrate-induced aplastic anemia, the estimated mortality rate for untreated aplastic anemia from any cause is between 20% and 30%. However, previous reports have shown a mortality rate as high as 70% for aplastic anemia, and the risk of death from this anemia generally varies with disease severity and cause. Although the majority of cases were in white women, risk factors for aplastic anemia in patients receiving filamide have not been identified. Whether patient age (to date, case range: 12–68 years), sex or race, duration of use, dosage, or concomitant use of other antiepileptic drugs or medications affects the probability of developing aplastic anemia in patients receiving filamide remains to be determined. Therefore, the manufacturer recommends that all patients receiving filamide should discontinue treatment and begin alternative therapy as needed unless the clinician determines that the benefit of continuing filamide treatment outweighs the risk of aplastic anemia. Of the 10 patients who developed acute liver failure during filamide treatment, 4 died and 1 underwent a liver transplant. Whether prior liver impairment increases the risk of fulminant hepatic failure is unclear; however, the manufacturer recommends that all patients be evaluated for liver impairment before starting filamide treatment and that the drug is not recommended for patients with a history of liver dysfunction. No other risk factors for acute liver failure in patients receiving filamide have been identified. The patient's age (to date, case range: 5–78 years), sex or race, duration of drug exposure, dose, or concomitant use of other antiepileptic drugs or medications may affect the probability of acute liver failure in patients receiving felbamate, which remains to be determined. For more complete data on drug warnings for 2-phenyl-1,3-propanediol dicarboxylate (29 in total), please visit the HSDB record page. Pharmacodynamics: Felbamate is an antiepileptic drug that can be used as monotherapy or in combination with other antiepileptic drugs to treat focal seizures caused by epilepsy. In vitro receptor binding studies have shown that felbamate has weak inhibitory effects on GABA and benzodiazepine receptor binding and is inactive at the MK-801 receptor binding site of the NMDA receptor-ionopeptide complex. However, felbamate can act as an antagonist by interacting with the glycine recognition site of the NMDA receptor-ionopeptide complex, which is insensitive to strychnine.

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1. Felbamate, as a gating regulator of NMDA receptors, exerts its inhibitory effect by selectively binding to the desensitized state of the channel rather than the resting or open state[1]
2. Use-dependent inhibition of felbamate suggests that it is more effective in inhibiting the overactivation of NMDA receptors (e.g., during seizures) without significantly affecting normal physiological NMDA receptor function[1]
3. The selective inhibition of NMDA receptors containing NR1/NR2B subunits by felbamate may contribute to its therapeutic effect, as the NR2B subunit is highly expressed in brain regions involved in epilepsy and pain signaling[2].
4. Felbamate does not compete with glutamate or glycine for binding sites on NMDA receptors, suggesting that the drug has a unique binding pocket[1][2].

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

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)

Solubility in Formulation 1: ≥ 2.75 mg/mL (11.54 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.75 mg/mL (11.54 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.75 mg/mL (11.54 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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