Peringatan Keamanan

Information on daily doses over 800 mg/day of zonisamide is limited. During clinical development, three patients ingested unknown amounts of zonisamide as suicide attempts, and all of them were hospitalized with central nervous system symptoms. One patient became comatose and developed bradycardia, hypotension, and respiratory depression; 31 hours after zonisamide ingestion, plasma level was 100.1 µg/mL. Zonisamide plasma levels fell with a half-life of 57 hours, and the patient became alert five days later.L42530,L42535 There are no specific antidotes for zonisamide overdosage. In case of a suspected recent overdose, emesis should be induced or gastric lavage performed with the usual precautions to protect the airway. General supportive care is indicated, including frequent monitoring of vital signs and close observation.L42530,L42535 Due to its long half-life and low protein binding, renal dialysis may be effective in treating zonisamide overdose; however, the effectiveness of this procedure has not been formally studied.L42535

In vivo studies found no evidence of carcinogenicity at zonisamide doses equivalent to or higher than the maximum recommended human dose (MRHD). In an in vitro chromosomal aberration assay in CHL cells, zonisamide displayed mutagenicity. Signs of reproductive toxicity were also detected in rats treated with a dose 0.5 times the MRHD.L42530,L42535

Zonisamide

DB00909

small molecule approved investigational

Deskripsi

Zonisamide is a sulfonamide anticonvulsant used as an adjunctive therapy in adults with partial-onset seizures.L42530,L42535 Zonisamide may act by blocking repetitive firing of voltage-gated sodium channels, leading to a reduction of T-type calcium channel currents or by binding allosterically to GABA receptors. This latter action may inhibit the uptake of the inhibitory neurotransmitter GABA while enhancing the uptake of the excitatory neurotransmitter glutamate.L42530,L42535 Zonisamide represents an alternative for patients that remain refractory to established antiepileptic drugs. In 1989, it was approved for commercial use in Japan. The US and Europe approved it in 2000 and 2005, respectively.A1379,A1383

Struktur Molekul 2D

Berat 212.226
Wujud solid

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) In plasma, the elimination half-life of zonisamide is approximately 63 hours. In red blood cells, it is approximately 105 hours.[L42530,L42535]
Volume Distribusi Following a 400 mg oral dose, zonisamide has an apparent volume of distribution (V/F) of 1.45 L/kg.[L42530,L42535]
Klirens (Clearance) In patients not taking enzyme-inducing antiepilepsy drugs (AEDs), the plasma clearance of oral zonisamide is approximately 0.30-0.35 mL/min/kg. In patients treated with AEDs, this value increases to 0.5 mL/min/kg.[L42530,L42535] Renal clearance is approximately 3.5 mL/min after a single-dose of zonisamide.[L42530,L42535] In red blood cells, the clearance of an oral dose of zonisamide is 2 mL/min.[L42530]

Absorpsi

Between 200 and 400 mg, zonisamide follows a dose-proportional pharmacokinetic profile.L42530,L42535 At concentrations higher than 800 mg, the Cmax and AUC increase in a disproportional manner, possibly due to zonisamide binding red blood cells. In healthy volunteers given 200 to 400 mg of zonisamide orally, peak plasma concentrations (Cmax) range between 2 and 5 µg/mL and are reached within 2–6 hours (Tmax).L42530 In healthy volunteers given 100 mg of zonisamide oral suspension, the Tmax ranged from 0.5 to 5 hours.L42535 Zonisamide has a high oral bioavailability (95%).A1383 The Tmax of zonisamide was delayed by food intake (4-6 hours); however, food has no effect on its bioavailability. Steady state is achieved 14 days after a stable dose is reached.L42530,L42535

Metabolisme

Zonisamide metabolites are generated mainly by principally reductive and conjugative mechanisms. Oxidation reactions play a minor role in the metabolism of zonisamide.A1383 Zonisamide is metabolized by N-acetyl-transferases to form N-acetyl zonisamide and reduced to form the open ring metabolite, 2–sulfamoylacetylphenol (SMAP). The reduction of zonisamide to SMAP is mediated by CYP3A4.A1379,A1383,L42530,L42535 Zonisamide does not induce liver enzymes or its own metabolism.A1379

Rute Eliminasi

Zonisamide is mainly excreted as the parent drug and the glucuronide of a metabolite. Urine is the main route of zonisamide excretion, and only a small portion of this drug is excreted in feces.A1379 Following multiple doses of radiolabeled zonisamide, 62% of the dose was recovered in the urine, and 3% in feces by day 10. Of the excreted dose of zonisamide, 35% was recovered unchanged, 15% as N-acetyl zonisamide, and 50% as the glucuronide of 2–sulfamoylacetylphenol (SMAP).L42530,L42535

Interaksi Makanan

2 Data
  • 1. Avoid alcohol. Ingesting alcohol may increase drowsiness and dizziness.
  • 2. Take with or without food.

Interaksi Obat

2232 Data
Afatinib The serum concentration of Afatinib can be increased when it is combined with Zonisamide.
Bosutinib The serum concentration of Bosutinib can be increased when it is combined with Zonisamide.
Brentuximab vedotin The serum concentration of Brentuximab vedotin can be increased when it is combined with Zonisamide.
Colchicine The serum concentration of Colchicine can be increased when it is combined with Zonisamide.
Edoxaban The serum concentration of Edoxaban can be increased when it is combined with Zonisamide.
Ledipasvir The serum concentration of Ledipasvir can be increased when it is combined with Zonisamide.
Naloxegol The serum concentration of Naloxegol can be increased when it is combined with Zonisamide.
Pazopanib The serum concentration of Pazopanib can be increased when it is combined with Zonisamide.
Prucalopride The serum concentration of Prucalopride can be increased when it is combined with Zonisamide.
Ranolazine The serum concentration of Ranolazine can be increased when it is combined with Zonisamide.
Silodosin The excretion of Silodosin can be decreased when combined with Zonisamide.
Topotecan The serum concentration of Topotecan can be increased when it is combined with Zonisamide.
Ceritinib Zonisamide may increase the bradycardic activities of Ceritinib.
Ivabradine Zonisamide may increase the bradycardic activities of Ivabradine.
Ruxolitinib Ruxolitinib may increase the bradycardic activities of Zonisamide.
Cilostazol The serum concentration of Cilostazol can be increased when it is combined with Zonisamide.
Buprenorphine Zonisamide may increase the central nervous system depressant (CNS depressant) activities of Buprenorphine.
Doxylamine Doxylamine may increase the central nervous system depressant (CNS depressant) activities of Zonisamide.
Dronabinol Dronabinol may increase the central nervous system depressant (CNS depressant) activities of Zonisamide.
Droperidol Droperidol may increase the central nervous system depressant (CNS depressant) activities of Zonisamide.
Hydrocodone Zonisamide may increase the central nervous system depressant (CNS depressant) activities of Hydrocodone.
Magnesium sulfate The therapeutic efficacy of Zonisamide can be increased when used in combination with Magnesium sulfate.
Methotrimeprazine Zonisamide may increase the central nervous system depressant (CNS depressant) activities of Methotrimeprazine.
Metyrosine Zonisamide may increase the sedative activities of Metyrosine.
Minocycline Minocycline may increase the central nervous system depressant (CNS depressant) activities of Zonisamide.
Mirtazapine Zonisamide may increase the central nervous system depressant (CNS depressant) activities of Mirtazapine.
Nabilone Nabilone may increase the central nervous system depressant (CNS depressant) activities of Zonisamide.
Orphenadrine Zonisamide may increase the central nervous system depressant (CNS depressant) activities of Orphenadrine.
Paraldehyde Zonisamide may increase the central nervous system depressant (CNS depressant) activities of Paraldehyde.
Perampanel Perampanel may increase the central nervous system depressant (CNS depressant) activities of Zonisamide.
Pramipexole Zonisamide may increase the sedative activities of Pramipexole.
Ropinirole Zonisamide may increase the sedative activities of Ropinirole.
Rotigotine Zonisamide may increase the sedative activities of Rotigotine.
Rufinamide The risk or severity of adverse effects can be increased when Rufinamide is combined with Zonisamide.
Sodium oxybate Zonisamide may increase the central nervous system depressant (CNS depressant) activities of Sodium oxybate.
Suvorexant Zonisamide may increase the central nervous system depressant (CNS depressant) activities of Suvorexant.
Tapentadol Tapentadol may increase the central nervous system depressant (CNS depressant) activities of Zonisamide.
Thalidomide Zonisamide may increase the central nervous system depressant (CNS depressant) activities of Thalidomide.
Zolpidem Zonisamide may increase the central nervous system depressant (CNS depressant) activities of Zolpidem.
Dabrafenib The serum concentration of Zonisamide can be decreased when it is combined with Dabrafenib.
Everolimus The serum concentration of Everolimus can be increased when it is combined with Zonisamide.
Rifaximin The serum concentration of Rifaximin can be increased when it is combined with Zonisamide.
Nicotine The risk or severity of adverse effects can be increased when Zonisamide is combined with Nicotine.
Mecamylamine The risk or severity of adverse effects can be increased when Zonisamide is combined with Mecamylamine.
Pentolinium The risk or severity of adverse effects can be increased when Zonisamide is combined with Pentolinium.
Trimethaphan The risk or severity of adverse effects can be increased when Zonisamide is combined with Trimethaphan.
Hexamethonium The risk or severity of adverse effects can be increased when Zonisamide is combined with Hexamethonium.
Cyclopentamine The risk or severity of adverse effects can be increased when Zonisamide is combined with Cyclopentamine.
Luliconazole The serum concentration of Zonisamide can be increased when it is combined with Luliconazole.
Mefloquine The therapeutic efficacy of Zonisamide can be decreased when used in combination with Mefloquine.
Mianserin The therapeutic efficacy of Zonisamide can be decreased when used in combination with Mianserin.
Orlistat Orlistat can cause a decrease in the absorption of Zonisamide resulting in a reduced serum concentration and potentially a decrease in efficacy.
Phenytoin Phenytoin may increase the excretion rate of Zonisamide which could result in a lower serum level and potentially a reduction in efficacy.
Fosphenytoin Fosphenytoin may increase the excretion rate of Zonisamide which could result in a lower serum level and potentially a reduction in efficacy.
Cimetidine The serum concentration of Zonisamide can be increased when it is combined with Cimetidine.
Clopidogrel The therapeutic efficacy of Clopidogrel can be decreased when used in combination with Zonisamide.
Efavirenz The serum concentration of Zonisamide can be decreased when it is combined with Efavirenz.
Melatonin The therapeutic efficacy of Zonisamide can be decreased when used in combination with Melatonin.
Nafcillin The therapeutic efficacy of Zonisamide can be decreased when used in combination with Nafcillin.
Nitroprusside Zonisamide may increase the hypotensive activities of Nitroprusside.
Flecainide The excretion of Flecainide can be decreased when combined with Zonisamide.
Memantine The excretion of Memantine can be decreased when combined with Zonisamide.
Quinine The excretion of Quinine can be decreased when combined with Zonisamide.
Methadone The risk or severity of adverse effects can be increased when Methadone is combined with Zonisamide.
Dantrolene The risk or severity of hyperkalemia can be increased when Dantrolene is combined with Zonisamide.
Lithium citrate The risk or severity of adverse effects can be increased when Zonisamide is combined with Lithium citrate.
Lithium carbonate The risk or severity of adverse effects can be increased when Zonisamide is combined with Lithium carbonate.
Lithium hydroxide The risk or severity of adverse effects can be increased when Zonisamide is combined with Lithium hydroxide.
Methotrexate The protein binding of Methotrexate can be increased when combined with Zonisamide.
Metformin The risk or severity of lactic acidosis can be increased when Zonisamide is combined with Metformin.
Zidovudine The metabolism of Zonisamide can be increased when combined with Zidovudine.
Testosterone propionate The metabolism of Zonisamide can be increased when combined with Testosterone propionate.
Tetracosactide The risk or severity of liver damage can be increased when Tetracosactide is combined with Zonisamide.
Boceprevir The serum concentration of Zonisamide can be increased when it is combined with Boceprevir.
Vincristine The excretion of Vincristine can be decreased when combined with Zonisamide.
Ethanol Zonisamide may increase the central nervous system depressant (CNS depressant) activities of Ethanol.
Azelastine Zonisamide may increase the central nervous system depressant (CNS depressant) activities of Azelastine.
Brimonidine Brimonidine may increase the central nervous system depressant (CNS depressant) activities of Zonisamide.
Duloxetine The risk or severity of adverse effects can be increased when Zonisamide is combined with Duloxetine.
Paroxetine The risk or severity of adverse effects can be increased when Zonisamide is combined with Paroxetine.
Sibutramine The risk or severity of adverse effects can be increased when Zonisamide is combined with Sibutramine.
Zimelidine The risk or severity of adverse effects can be increased when Zonisamide is combined with Zimelidine.
Dapoxetine The risk or severity of adverse effects can be increased when Zonisamide is combined with Dapoxetine.
Milnacipran The risk or severity of adverse effects can be increased when Zonisamide is combined with Milnacipran.
Desvenlafaxine The risk or severity of adverse effects can be increased when Zonisamide is combined with Desvenlafaxine.
Seproxetine The risk or severity of adverse effects can be increased when Zonisamide is combined with Seproxetine.
Levomilnacipran Zonisamide may decrease the excretion rate of Levomilnacipran which could result in a higher serum level.
Indalpine The risk or severity of adverse effects can be increased when Zonisamide is combined with Indalpine.
Ritanserin The risk or severity of adverse effects can be increased when Zonisamide is combined with Ritanserin.
Alaproclate The risk or severity of adverse effects can be increased when Zonisamide is combined with Alaproclate.
Escitalopram The metabolism of Escitalopram can be decreased when combined with Zonisamide.
Sertraline The risk or severity of adverse effects can be increased when Zonisamide is combined with Sertraline.
Doxorubicin The serum concentration of Doxorubicin can be increased when it is combined with Zonisamide.
Lumacaftor The serum concentration of Zonisamide can be decreased when it is combined with Lumacaftor.
Dexketoprofen The risk or severity of adverse effects can be increased when Dexketoprofen is combined with Zonisamide.
Ketoprofen The risk or severity of adverse effects can be increased when Ketoprofen is combined with Zonisamide.
Methenamine The serum concentration of the active metabolites of Methenamine can be reduced when Methenamine is used in combination with Zonisamide resulting in a loss in efficacy.
Quinidine Quinidine may increase the arrhythmogenic activities of Zonisamide.
Carteolol Zonisamide may increase the arrhythmogenic activities of Carteolol.
Tocainide Zonisamide may increase the arrhythmogenic activities of Tocainide.

Target Protein

Sodium channel protein type 1 subunit alpha SCN1A
Sodium channel protein type 2 subunit alpha SCN2A
Sodium channel protein type 3 subunit alpha SCN3A
Sodium channel protein type 4 subunit alpha SCN4A
Sodium channel protein type 5 subunit alpha SCN5A
Sodium channel protein type 9 subunit alpha SCN9A
Sodium channel protein type 11 subunit alpha SCN11A
Sodium channel regulatory subunit beta-1 SCN1B
Sodium channel regulatory subunit beta-2 SCN2B
Sodium channel regulatory subunit beta-3 SCN3B
Sodium channel regulatory subunit beta-4 SCN4B
Voltage-dependent T-type calcium channel subunit alpha-1G CACNA1G
Voltage-dependent T-type calcium channel subunit alpha-1H CACNA1H
Voltage-dependent T-type calcium channel subunit alpha-1I CACNA1I
Carbonic anhydrase 1 CA1
Carbonic anhydrase 2 CA2
Carbonic anhydrase 3 CA3
Carbonic anhydrase 4 CA4
Carbonic anhydrase 5A, mitochondrial CA5A
Carbonic anhydrase 5B, mitochondrial CA5B
Carbonic anhydrase 6 CA6
Carbonic anhydrase 7 CA7
Carbonic anhydrase-related protein CA8
Carbonic anhydrase 9 CA9
Carbonic anhydrase-related protein 10 CA10
Carbonic anhydrase-related protein 11 CA11
Carbonic anhydrase 12 CA12
Carbonic anhydrase 13 CA13
Carbonic anhydrase 14 CA14
Amine oxidase [flavin-containing] B MAOB
Amine oxidase [flavin-containing] A MAOA
GABA(A) Receptor Benzodiazepine Binding Site GABRA1

Referensi & Sumber

Synthesis reference: Nidam, T. et al. Novel sulfonation method for zonisamide intermediate in zonisamide synthesis and their novel crystal forms. (2003) U.S. Patent US 2003/0144527 A1. Available at: https://patentimages.storage.googleapis.com/25/24/0f/19d95f38252d52/US20030144527A1.pdf
Artikel (PubMed)
  • PMID: 15511691
    Leppik IE: Zonisamide: chemistry, mechanism of action, and pharmacokinetics. Seizure. 2004 Dec;13 Suppl 1:S5-9; discussion S10.
  • PMID: 12941455
    Ueda Y, Doi T, Tokumaru J, Willmore LJ: Effect of zonisamide on molecular regulation of glutamate and GABA transporter proteins during epileptogenesis in rats with hippocampal seizures. Brain Res Mol Brain Res. 2003 Aug 19;116(1-2):1-6.
  • PMID: 20001433
    Schulze-Bonhage A: Zonisamide in the treatment of epilepsy. Expert Opin Pharmacother. 2010 Jan;11(1):115-26. doi: 10.1517/14656560903468728.
  • PMID: 18433351
    Kothare SV, Kaleyias J: Zonisamide: review of pharmacology, clinical efficacy, tolerability, and safety. Expert Opin Drug Metab Toxicol. 2008 Apr;4(4):493-506. doi: 10.1517/17425255.4.4.493 .
  • PMID: 7686468
    Peters DH, Sorkin EM: Zonisamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy. Drugs. 1993 May;45(5):760-87.
  • PMID: 14704463
    Sobieszek G, Borowicz KK, Kimber-Trojnar Z, Malek R, Piskorska B, Czuczwar SJ: Zonisamide: a new antiepileptic drug. Pol J Pharmacol. 2003 Sep-Oct;55(5):683-9.

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