Levetiracetam inhibits the activity of O6-methylguanine-DNA-methyltransferase (MGMT) by increasing HDAC transcription and enlisting corepressor complexes on the promoter [1]. Glioblastoma multiforme stem-like cells (GSC) are made more sensitive to temozolomide (250 μM) treatment by levetiracetam (40 μg/mL) [1]. Levetiracetam (40 μg/mL) treatment of GCSCs results in down-regulated MGMT expression[1].

Levetiracetam (10, 25, or 50 mg/kg) suppresses EEG and behavioral seizure activity in neonates experiencing hypoxia [2].

Cell Viability Assay[1]
Cell Types: GCSC neurospheres
Tested Concentrations: 40 μg/mL
Incubation Duration: 48 hrs (hours)
Experimental Results: Slight antitumor effect exerted by the treatment with Temozolomide (250 µM) or Levetiracetam (40 μg/mL) alone was strongly enhanced when Temozolomide and Levetiracetam were added in combination.

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Western Blot Analysis[1]
Cell Types: Glioblastoma multiforme stem-like cells (GSCs)
Tested Concentrations: 40 μg/mL
Incubation Duration: 48 hrs (hours)
Experimental Results: A high level of MGMT expression in untreated GCSCs; this expression was slightly diminished after treatment with Temozolomide (250 µM) and Levetiracetam singularly but it was dramatically diminished after the combined treatment with Temozolomide and Levetiracetam.

Animal/Disease Models: Male Long-Evans rats[2]
Doses: 10, 25, or 50 mg/kg
Route of Administration: intraperitoneal (ip)injection 60 min before hypoxia.
Experimental Results: Treatment resulted in a significant decrease in hypoxic seizure (HS) duration at 25 mg/ kg and at 50 mg/kg. Anticonvulsant activity was maximal at 50 mg/kg, at which HSs were decreased by 63.6%.

Absorption, Distribution and Excretion
Levetiracetam is rapidly and nearly completely absorbed following oral administration, with a reported absolute oral bioavailability of essentially 100%. Tmax is approximately 1.3 hours after dosing, and Cmax is 31 μg/mL following a single 1000mg dose and 43 μg/mL following repeated dosing. Co-administration of levetiracetam with food delays Tmax by approximately 1.5 hours and decreases Cmax by 20%.
Approximately 66% of the administered dose of levetiracetam is excreted in the urine as unchanged drug, while only 0.3% of the total dose is excreted via the feces. The primary inactive metabolite of levetiracetam, L057, is also found in the urine as approximately 24% of the administered dose.
The volume of distribution of levetiracetam is approximately 0.5 to 0.7 L/kg.
The total plasma clearance of levetiracetam is 0.96 mL/min/kg, with renal clearance comprising 0.6 mL/min/kg. The primary inactive metabolite of levetiracetam, L057, has a renal clearance of 4 mL/min/kg. Given the relatively high proportion of drug undergoing renal clearance, overall clearance of levetiracetam is reduced in patients with renal impairment.
Absorption of levetiracetam is rapid, with peak plasma concentrations occurring in about an hour following oral administration in fasted subjects. The oral bioavailability of levetiracetam tablets is 100% and the tablets and oral solution are bioequivalent in rate and extent of absorption. Food does not affect the extent of absorption of levetiracetam but it decreases C max by 20% and delays T max by 1.5 hours.
The pharmacokinetics of levetiracetam are linear over the dose range of 500-5000 mg. Steady state is achieved after 2 days of multiple twice-daily dosing.
Levetiracetam is not significantly protein-bound (<10% bound) and its volume of distribution is close to the volume of intracellular and extracellular water.
Levetiracetam C max and AUC were 20% higher in women (N=11) compared to men (N=12). However, clearances adjusted for body weight were comparable.
For more Absorption, Distribution and Excretion (Complete) data for LEVETIRACETAM (12 total), please visit the HSDB record page.

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Metabolism / Metabolites
Levetiracetam is minimally metabolized within the body - the major metabolic pathway appears to be the enzymatic hydrolysis of its acetamide group which produces an inactive carboxylic acid metabolite, L057, which accounts for approximately 24% of the total administered dose. The specific enzyme(s) responsible for this reaction are unclear, but this pathway is known to be independent of hepatic CYP enzymes and has been proposed to be driven primarily by type B esterases in the blood and other tissues. Two minor metabolites involving modifications to the pyrrolidone ring have been identified, one involving hydroxylation of the ring (constituting 1.6% of the total dose) and the other involving opening of the ring structure (constituting 0.9% of the total dose).
Levetiracetam is not extensively metabolized in humans. The major metabolic pathway is the enzymatic hydrolysis of the acetamide group, which produces the carboxylic acid metabolite, ucb L057 (24% of dose) and is not dependent on any liver cytochrome P450 isoenzymes. The major metabolite is inactive in animal seizure models. Two minor metabolites were identified as the product of hydroxylation of the 2-oxo-pyrrolidine ring (2% of dose) and opening of the 2-oxo-pyrrolidine ring in position 5 (1% of dose). There is no enantiomeric interconversion of levetiracetam or its major metabolite.

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Biological Half-Life
The plasma half-life of levetiracetam is 6-8 hours and is not affected by dose or repeat administration. Half-life is increased in the elderly (by about 40%) and those with renal impairment.
... The plasma elimination half-life of the unchanged drug varied between 7.4 hr and 7.9 hr. ...
Levetiracetam plasma half-life in adults is 7 +/-1 hour and is unaffected by either dose or repeated administration.

Interactions
No interaction between probenecid and levetiracetam was observed; however, probenecid decreased the renal clearance of ucb L057 (inactive metabolite of levetiracetam) by 60%.
/Levetiracetam/ had no effect on the pharmacokinetic disposition of phenytoin in patients with refractory epilepsy. Pharmacokinetics of levetiracetam were also not affected by phenytoin.
Levetiracetam did not alter the pharmacokinetics of valproate in healthy volunteers. Valproate 500 mg twice daily did not modify the rate or extent of levetiracetam absorption or its plasma clearance or urinary excretion. There also was no effect on exposure to and the excretion of the primary metabolite, ucb L057. Potential drug interactions between /levetiracetam/ and other Antiepileptic Drugs (AEDs) (carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone and valproate) were also assessed by evaluating the serum concentrations of levetiracetam and these AEDs during placebo-controlled clinical studies. These data indicate that levetiracetam does not influence the plasma concentration of other AEDs and that these AEDs do not influence the pharmacokinetics of levetiracetam.
/Levetiracetam/ did not influence the pharmacokinetics and pharmacodynamics (ECG) of digoxin given as a 0.25 mg dose every day. Coadministration of digoxin did not influence the pharmacokinetics of levetiracetam.
For more Interactions (Complete) data for LEVETIRACETAM (7 total), please visit the HSDB record page.

[1]. Levetiracetam enhances the temozolomide effect on glioblastoma stem cell proliferation and apoptosis. Cancer Cell Int. 2018 Sep 10;18:136.

[2]. Antiepileptic effects of levetiracetam in a rodent neonatal seizure model. Pediatr Res. 2013 Jan;73(1):24-30.

Therapeutic Uses
Levetiracetam is indicated as adjunctive therapy in the treatment of partial onset seizures in adults and children 4 years of age and older with epilepsy. /included in US product labe/

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Drug Warnings
Adverse neuropsychiatric effects reported during levetiracetam treatment are classified into 3 categories: somnolence and fatigue, coordination difficulties, and behavioral changes. In controlled studies, 14.8% of patients who received levetiracetam experienced somnolence compared with 8.4% of placebo-treated patients, and about 3% of levetiracetam-treated patients discontinued treatment due to somnolence. About 14.7% of patients who received levetiracetam experienced asthenia compared with 9.1% of placebo-treated patients, and 0.8% of levetiracetam-treated patients discontinued treatment due to asthenia. Coordination difficulties were experienced by 3.4% of levetiracetam patients compared with 1.6% of placebo-treated patients. Somnolence, asthenia, and coordination difficulties occurred most frequently within the first 4 weeks of treatment. Psychotic manifestations and hallucinations were reported rarely in patients receiving levetiracetam in clinical studies. Other behavioral symptoms (e.g., agitation, hostility, anxiety, apathy, emotional lability, depersonalization, depression, aggression, anger, irritability) occurred in 13.3% of levetiracetam-treated patients in clinical studies compared with 6.2% of placebo patients, and 1.7% of levetiracetam-treated patients discontinued treatment because of these events.
Because of the possibility of increased seizure frequency, anticonvulsant drugs, including levetiracetam, should not be discontinued suddenly. Levetiracetam should be withdrawn gradually by reducing the dosage by 1g daily at 2-week intervals.
Adverse effects occurring in 1% or more of patients receiving levetiracetam and more frequently than placebo include somnolence, asthenia, headache, infection, dizziness, pain, pharyngitis, depression, nervousness, rhinitis, anorexia, ataxia, vertigo, amnesia, anxiety, emotional lability, hostility, paresthesia, increased cough, sinusitis, and diplopia and were reported in clinical studies in which levetiracetam was administered in conjunction with other anticonvulsants. Asthenia, somnolence, and dizziness occurred predominantly during the initial 4 weeks of treatment.
Minor decreases in total mean erythrocyte count, mean hemoglobin, and mean hematocrit have been reported. Leukopenia, neutropenia, pancytopenia (with myelosuppression in some cases), and thrombocytopenia also have been observed, although a causal relationship to the drug has not been established.
For more Drug Warnings (Complete) data for LEVETIRACETAM (12 total), please visit the HSDB record page.

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Pharmacodynamics
Levetiracetam appears to prevent seizure activity via the selective inhibition of hypersynchronized epileptiform burst firing without affecting normal neuronal transmission, though the exact mechanism through which this occurs is unclear. The therapeutic index of levetiracetam is wide, making it relatively unique amongst other anti-epileptic medications. Anti-epileptic drugs, including levetiracetam, may increase the risk of suicidal ideation or behaviour - patients taking levetiracetam should be monitored for the emergence or worsening of depressive symptoms, suicidal ideation, and behavioural abnormalities.

C8H14N2O2

170.21

170.105

102767-28-2

Etiracetam;33996-58-6

5284583

White to off-white solid powder

1.2±0.1 g/cm3

395.9±25.0 °C at 760 mmHg

118-119°C

193.2±23.2 °C

0.0±0.9 mmHg at 25°C

1.519

-0.67

1

2

3

12

203

1

CC[C@@H](C(=O)N)N1CCCC1=O

HPHUVLMMVZITSG-LURJTMIESA-N

InChI=1S/C8H14N2O2/c1-2-6(8(9)12)10-5-3-4-7(10)11/h6H,2-5H2,1H3,(H2,9,12)/t6-/m0/s1

(S)-2-(2-oxopyrrolidin-1-yl)butanamide

Levetiracetam, UCBL059, UCB L059, UCB-L059, SIB S1, SIBS1, SIB-S1, Keppra, Etiracetam, UCB6474, UCB-6474, UCB 6474,

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: ≥ 2.5 mg/mL (14.69 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 25.0 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: ≥ 2.5 mg/mL (14.69 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 25.0 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: ≥ 2.5 mg/mL (14.69 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: Saline: 30 mg/mL

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Solubility in Formulation 5: 100 mg/mL (587.51 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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