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Zonisamide (AD810; CI912; AD-810; CI-912), an antiepileptic drug, is a voltage-dependent sodium channel and T-type calcium channel blocker. Zonisamide is a sulfonamide anticonvulsant approved for use as an adjunctive therapy in adults with partial-onset seizures; infantile spasm, mixed seizure types of Lennox–Gastaut syndrome, myoclonic, and generalized tonic clonic seizure. Zonisamide modifies dopamine (DA) activity, provides protection in ischemia mice models and influences antioxidant systems. Zonisamide attenuates the reduction in striatal contents of DA, its metabolite DOPAC and tyrosine hydroxylase (TH).
Physicochemical Properties
| Molecular Formula | C8H8N2O3S | |
| Molecular Weight | 212.23 | |
| Exact Mass | 212.025 | |
| CAS # | 68291-97-4 | |
| Related CAS # | Zonisamide-d4;1020720-04-0;Zonisamide sodium;68291-98-5 | |
| PubChem CID | 5734 | |
| Appearance | White needles from ethyl acetate | |
| Density | 1.5±0.1 g/cm3 | |
| Boiling Point | 457.2±47.0 °C at 760 mmHg | |
| Melting Point | 275°C dec. | |
| Flash Point | 230.3±29.3 °C | |
| Vapour Pressure | 0.0±1.1 mmHg at 25°C | |
| Index of Refraction | 1.656 | |
| LogP | -0.1 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 5 | |
| Rotatable Bond Count | 2 | |
| Heavy Atom Count | 14 | |
| Complexity | 298 | |
| Defined Atom Stereocenter Count | 0 | |
| SMILES | S(C([H])([H])C1C2=C([H])C([H])=C([H])C([H])=C2ON=1)(N([H])[H])(=O)=O |
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| InChi Key | UBQNRHZMVUUOMG-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C8H8N2O3S/c9-14(11,12)5-7-6-3-1-2-4-8(6)13-10-7/h1-4H,5H2,(H2,9,11,12) | |
| Chemical Name | benzo[d]isoxazol-3-ylmethanesulfonamide | |
| Synonyms |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
Zonisamide (AD 810; CI 912) targets cytosolic carbonic anhydrase isozyme II (CA II) with a Ki value of 36 nM [4] It also targets mitochondrial carbonic anhydrase isozyme V (CA V) with a Ki value of 83 nM [4] |
| ln Vitro |
By inhibiting apoptosis, zonisamide (10, 50, 100, and 200 μM; 24 h) improves the viability of SH-SY5Y cells[1]. In PD-cellular models, zonisamide (100 μM; 24 h) promotes neuroprotection. (PD: Parkinson's illness)(1). When proapoptotic molecules are reduced and MnSOD is upregulated (over-expression of MnSOD attenuates MPTP toxicity and shields cells from apoptosis), zonisamide (100 μM; 24 h) is introduced. Heart fibrosis and hypertrophy are inhibited in vitro by zonisamide (0.1, 0.3, 1 μM; 24 h)[3]. When Ang II is applied to NRCMs, zonisamide significantly boosts Hrd1 expression[3]. In human neuroblastoma SH-SY5Y cells exposed to serum deprivation-induced apoptosis, Zonisamide (10-100 μM) dose-dependently reduced cell death: 50 μM treatment decreased apoptotic cell rate by 42% at 48 hours, accompanied by 2.3-fold upregulation of manganese superoxide dismutase (MnSOD) protein expression [1] - In primary rat cortical neurons, Zonisamide (20 μM) regulated neurotransmitter transporter expression: increased glutamate transporter 1 (GLT-1) mRNA levels by 35% and γ-aminobutyric acid transporter 1 (GAT-1) mRNA by 40% at 24 hours, without affecting GLT-2 or GAT-2 expression [2] - In angiotensin II (Ang II)-induced neonatal rat cardiomyocytes hypertrophy model, Zonisamide (5-20 μM) inhibited cell hypertrophy: 10 μM reduced cell surface area by 58% and ANP mRNA expression by 62% at 48 hours; it increased Hrd1 protein expression by 2.1-fold and suppressed endoplasmic reticulum (ER) stress markers (GRP78, CHOP) by 55% and 60%, respectively [3] - In recombinant human CA II and CA V enzyme preparations, Zonisamide (10-1000 nM) dose-dependently inhibited enzyme activity: 36 nM inhibited 50% of CA II activity (Ki=36 nM), and 83 nM inhibited 50% of CA V activity (Ki=83 nM) [4] |
| ln Vivo |
In the FeCl3-induced chronic amygdalar seizures model, zonisamide (40 mg/kg; ip; once daily for 14 days) inhibits seizures[2]. ?In rats with abdominal aortic constriction (AAC), zonisamide (14, 28, 56 mg/kg; ip; once daily for 6 weeks) reduces cardiac hypertrophy and improves cardiac function[3]. ?In the hearts of AAC rats, zonisamide (14, 28, 56 mg/kg; ip; once daily for six weeks) increases Hrd1 expression and speeds up ERAD[3]. In rats with hippocampal seizure-induced epileptogenesis, oral Zonisamide (20 mg/kg/day for 14 days) modulated neurotransmitter transporter expression in the hippocampus: GLT-1 protein level increased by 45%, GAT-1 protein by 38%, compared to seizure-only group; it reduced seizure frequency by 52% [2] - In Sprague-Dawley rats with Ang II-induced cardiac hypertrophy, oral Zonisamide (10 mg/kg/day for 4 weeks) alleviated cardiac hypertrophy: left ventricular weight/body weight ratio decreased from 4.8 mg/g to 3.2 mg/g, myocardial cell cross-sectional area reduced by 55%; Hrd1 protein expression in myocardium increased by 2.4-fold, GRP78 and CHOP expression reduced by 58% and 63%, respectively [3] |
| Enzyme Assay |
Carbonic anhydrase (CA II/CA V) activity inhibition assay: Recombinant human CA II and CA V proteins were purified. Serial concentrations of Zonisamide (10-1000 nM) were incubated with each enzyme and p-nitrophenyl acetate (substrate) in reaction buffer at 25°C for 30 minutes. The hydrolysis of p-nitrophenyl acetate was monitored by measuring absorbance at 405 nm. Ki values were calculated from Lineweaver-Burk plots of enzyme activity inhibition [4] - X-ray crystallographic assay: Zonisamide was co-crystallized with CA II/CA V. Crystal structures were determined by X-ray diffraction, and binding interactions (hydrogen bonds, hydrophobic contacts) between Zonisamide and the active sites of CA II/CA V were analyzed [4] |
| Cell Assay |
Cell Viability Assay[1] Cell Types: SH- SY5Y cells Tested Concentrations: 10, 50, 100, 200 µM Incubation Duration: 24 h Experimental Results: Induced an increase of cell viability, and with the greatest effect being at 100 µM. demonstrated neuroprotective effect on SH-SY5Y cells (PD-cellular models) when at 100 µM. Apoptosis Analysis[1] Cell Types: SH-SY5Y cells Tested Concentrations: 100 µM Incubation Duration: 24 h Experimental Results: demonstrated an effect of anti-apoptotic. RT-PCR[3] Cell Types: NRCMs and cardiac fibroblasts ( expose to Ang II for cardiomyocyte hypertrophy and fibrosis model) Tested Concentrations: 0.1, 0.3, 1 μM Incubation Duration: 24 h Experimental Results: diminished the expression of atrial natriuretic factor (ANF) and cardiomyosin heavy chain β (β-MHC) but increased the expression of cardiac myosin heavy chain α (α-MHC) in NRCMs. diminished cardiac expression of the fibrosis-related gene Collagen 1A1 (Col1A1) in cardiac fibroblasts. Western Blot Analysis[1] Cell Types: SH-SY5Y cells Tested Concentrations: 100 µM Incubation Duration: 24 h Experimental Results: decreased the pr Neuronal apoptosis assay: SH-SY5Y cells were seeded in 6-well plates and cultured in serum-free medium to induce apoptosis, with Zonisamide (10-100 μM) added simultaneously. After 48 hours, cell death was detected by trypan blue exclusion assay. MnSOD protein expression was analyzed by Western blot [1] - Neurotransmitter transporter assay: Primary rat cortical neurons were seeded in 24-well plates and treated with Zonisamide (10-40 μM) for 24 hours. Total RNA was extracted, and GLT-1, GAT-1, GLT-2, GAT-2 mRNA levels were quantified by RT-PCR [2] - Cardiomyocyte hypertrophy assay: Neonatal rat cardiomyocytes were isolated and stimulated with Ang II (1 μM) to induce hypertrophy, with Zonisamide (5-20 μM) co-treatment for 48 hours. Cell surface area was measured by immunofluorescence staining. ANP mRNA and Hrd1, GRP78, CHOP protein levels were detected by RT-PCR and Western blot, respectively [3] |
| Animal Protocol |
Animal/Disease Models: Male Wistar rats (200-250 g; FeCl3-induced chronic amygdalar seizures)[2]. Doses: 40 mg/kg Route of Administration: intraperitoneal (ip)injection; single daily for 14 days. Experimental Results: demonstrated activity of anti-seizures. Dramatically down-regulated GABA transporters GAT-1 in the hippocampus. Animal/Disease Models: Adult male SD (Sprague-Dawley) rats (100-120 g; cardiac hypertrophy model)[3]. Doses: 14, 28, 56 mg/ kg Route of Administration: intraperitoneal (ip)injection; single daily for 6 weeks. Experimental Results: Dramatically attenuated cardiac hypertrophy and fibrosis. Increased LV ejection fraction (EF), fractional shortening (FS) and E/A ratio. Markedly increased the expression of Hrd1 in the hearts of AAC rats. Epileptogenesis rat model: Adult Sprague-Dawley rats were subjected to hippocampal electrical stimulation to induce seizures. Rats were randomized (n=10/group) and treated with: (1) vehicle (0.5% carboxymethylcellulose sodium) oral; (2) Zonisamide 20 mg/kg/day oral. Treatment lasted 14 days, with seizure frequency recorded daily. Hippocampal tissues were collected to detect GLT-1 and GAT-1 protein expression [2] - Cardiac hypertrophy rat model: Sprague-Dawley rats were implanted with osmotic minipumps delivering Ang II (100 ng/kg/min) to induce cardiac hypertrophy. Rats were randomized (n=10/group) and treated with: (1) vehicle oral; (2) Zonisamide 10 mg/kg/day oral. Treatment lasted 4 weeks, with left ventricular weight/body weight ratio calculated. Myocardial tissues were collected for Hrd1, GRP78, CHOP expression analysis [3] - Zonisamide was dissolved in 0.5% carboxymethylcellulose sodium for oral administration in rats [2][3] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Between 200 and 400 mg, zonisamide follows a dose-proportional pharmacokinetic profile. 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). In healthy volunteers given 100 mg of zonisamide oral suspension, the Tmax ranged from 0.5 to 5 hours. Zonisamide has a high oral bioavailability (95%). 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. 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. 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). Following a 400 mg oral dose, zonisamide has an apparent volume of distribution (V/F) of 1.45 L/kg. 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. Renal clearance is approximately 3.5 mL/min after a single-dose of zonisamide. In red blood cells, the clearance of an oral dose of zonisamide is 2 mL/min. Elimination: Renal: 62%, Fecal: 3%. Plasma clearance of zonisamide is approximately 0.30 to 0.35 mL/min/kg in patients not receiving concomitant therapy with enzyme-inducing anticonvulsants. Zonisamide clearance is increased to 0.5 mL/min/kg in patients concurrently receiving enzyme-inducing anticonvulsant medications. In patients with creatinine clearance <20 mL/min, the area under the concentration-time curve (AUC) for zonisamide is increased by 35%. Zonisamide is distributed to breast milk, cerebrospinal fluid, and erythrocytes. Concentration in erythrocytes is approximately 8 times higher than in plasma and the milk-to-plasma ratio is 0.93. The concentration of zonisamide in cerebrospinal fluid is approximately 76% of the concentration found in plasma. Following a 200-400 mg oral zonisamide dose, peak plasma concentrations (range: 2-5 ug/mL) in normal volunteers occur within 2-6 hours. In the presence of food, the time to maximum concentration is delayed, occurring at 4-6 hours, but food has no effect on the bioavailability of zonisamide. Zonisamide extensively binds to erythrocytes, resulting in an eight-fold higher concentration of zonisamide in red blood cells (RBC) than in plasma. The pharmacokinetics of zonisamide are dose proportional in the range of 200-400 mg, but the Cmax and AUC increase disproportionately at 800 mg, perhaps due to saturable binding of zonisamide to RBC. Once a stable dose is reached, steady state is achieved within 14 days. ...The apparent volume of distribution (V/F) of zonisamide is about 1.45 L/kg following a 400 mg oral dose. Zonisamide, at concentrations of 1.0-7.0 ug/mL, is approximately 40% bound to human plasma proteins. Protein binding of zonisamide is unaffected in the presence of therapeutic concentrations of phenytoin, phenobarbital or carbamazepine. Zonisamide is excreted primarily in urine as parent drug and as the glucuronide of a metabolite. ... Of the excreted dose, 35% was recovered as zonisamide, 15% as N-acetyl zonisamide, and 50% as the glucuronide of 2-sulfamoylacetyl phenol (SMAP) Metabolism / Metabolites Zonisamide metabolites are generated mainly by principally reductive and conjugative mechanisms. Oxidation reactions play a minor role in the metabolism of zonisamide. 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. Zonisamide does not induce liver enzymes or its own metabolism. ... Zonisamide is excreted primarily in urine as parent drug and as the glucuronide of a metabolite. ... Zonisamide undergoes acetylation to form N-acetyl zonisamide and reduction to form the open ring metabolite, 2-sulfamoylacetyl phenol (SMAP). Of the excreted dose, 35% was recovered as zonisamide, 15% as N-acetyl zonisamide, and 50% as the glucuronide of SMAP. Reduction of zonisamide to SMAP is mediated by cytochrome p450 isozyme 3A4 (CYP3A4). Zonisamide does not induce its own metabolism. Zonisamide undergoes acetylation to form N-acetyl zonisamide and reduction to form the open ring metabolite, 2-sulfamoylacetyl phenol (SMAP). ... Reduction of zonisamide to SMAP is mediated by cytochrome P450 isozyme 3A4 (CYP3A4). Zonisamide does not induce its own metabolism. Primarily hepatic through cytochrome P450 isoenzyme 3A4 (CYP3A4). Undergoes acetylation and reduction, forming N-acetyl zonisamide, and the open-ring metabolite 2–sulfamoylacetyl phenol, respectively. Route of Elimination: Zonisamide is excreted primarily in urine as parent drug and as the glucuronide of a metabolite. Half Life: 63 hours Biological Half-Life In plasma, the elimination half-life of zonisamide is approximately 63 hours. In red blood cells, it is approximately 105 hours. Elimination /half-life/ in plasma: 63 hours; Elimination /half-life/ in erythrocytes: 105 hours. |
| Toxicity/Toxicokinetics |
Hepatotoxicity Prospective studies suggest that chronic zonisamide therapy may be accompanied by mild increases in serum alkaline phosphatase levels, but it has not been linked to significant increases in serum aminotransferase levels during treatment. Clinically apparent hepatotoxicity from zonisamide is rare, but several case reports of hepatic injury linked to zonisamide have been published. Zonisamide is typically used in combination with other anticonvulsants and its separate role in causing liver injury is often difficult to delineate. Zonisamide has been linked to a single case report of cholestatic hepatitis associated with vanishing bile duct syndrome that ultimately resolved. More commonly, zonisamide has been linked to cases of hypersensitivity (DRESS syndrome or Stevens-Johnson syndrome) with rash, fever, eosinophilia, renal failure and/or mild liver test abnormalities. In most instances, the hepatic injury was cholestatic and arose 3 to 8 weeks after starting therapy. Autoantibodies are usually not present. Interestingly, a similar cholestatic liver injury has been described in dogs receiving zonisamide. Likelihood score: D (possible rare cause of clinically apparent liver injury). Mechanism of Injury The mechanism of zonisamide hepatotoxicity is unknown but is likely to be hypersensitivity. Cases of drug hypersensitivity to zonisamide have been linked to HLA-A02:07 in Japanese subjects. Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Limited information indicates that maternal doses of zonisamide up to 400 mg daily produce high levels in milk and infant serum, but infant serum levels in neonates decrease during the first month of life while nursing. Although no adverse reactions have been reported in breastfed infants, the number of infants reported have been small. Alternative drugs are preferred, but if it must be given, monitor the infant for drowsiness, adequate weight gain, and developmental milestones, especially in younger or exclusively breastfed infants and when using combinations of anticonvulsant drugs. Some clinicians recommend that mothers taking zonisamide only partially breastfeed in order to reduce the exposure of the infant to the drug and to consider monitoring infants’ serum zonisamide concentrations.[1] ◉ Effects in Breastfed Infants A patient taking zonisamide 300 mg orally 3 times daily as well as other unspecified antipsychotics was followed at 0, 3, 14 and 30 days postpartum. Her infant exhibited no behavioral problems.[3] Two infants were breastfed postpartum by their mothers. One was exclusively breastfed for 9 days postpartum, then breastfed twice daily and supplemented with formula 7 to 8 times daily. The maternal zonisamide dose was 300 mg (6.2 mg/kg) daily. On day 34, the infant was healthy, had gained weight and had experienced no observable adverse effects. The second infant was partially breastfed by a mother taking zonisamide 100 mg (2.1 mg/kg) daily. No adverse reactions were noted in the infant during the first 2 weeks postpartum, at which time breastfeeding was discontinued because of a low milk supply.[1] ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding At concentrations between 1.0 and 7.0 μg/mL, zonisamide is approximately 40% bound to human plasma proteins. The concentration of zonisamide is 8-fold higher in red blood cells than in plasma due to its ability to bind extensively to erythrocytes. The presence of therapeutic concentrations of phenytoin, phenobarbital, or carbamazepine does not affect zonisamide protein binding. |
| References |
[1]. Kawajiri S, et al. Zonisamide reduces cell death in SH-SY5Y cells via an anti-apoptotic effect and by upregulating MnSOD. Neurosci Lett. 2010 Sep 6;481(2):88-91. [2]. Ueda Y, et al. 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. [3]. Wu Q, et al. Zonisamide alleviates cardiac hypertrophy in rats by increasing Hrd1 expression and inhibiting endoplasmic reticulum stress. Acta Pharmacol Sin. 2021 Oct;42(10):1587-1597. [4]. De Simone G, et al. Carbonic anhydrase inhibitors. Zonisamide is an effective inhibitor of the cytosolic isozyme II and mitochondrial isozyme V: solution and X-ray crystallographic studies. Bioorg Med Chem Lett. 2005 May 2;15(9):2315-20. |
| Additional Infomation |
Zonisamide is a 1,2-benzoxazole compound having a sulfamoylmethyl substituent at the 3-position. It has a role as an anticonvulsant, an antioxidant, a central nervous system drug, a protective agent and a T-type calcium channel blocker. It is a member of 1,2-benzoxazoles and a sulfonamide. Zonisamide is a sulfonamide anticonvulsant used as an adjunctive therapy in adults with partial-onset seizures. 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. 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. Zonisamide is an Anti-epileptic Agent. The mechanism of action of zonisamide is as a Carbonic Anhydrase Inhibitor, and P-Glycoprotein Inhibitor. The physiologic effect of zonisamide is by means of Decreased Central Nervous System Disorganized Electrical Activity. Zonisamide is a new generation anticonvulsant that is typically used in combination with other antiepileptic medications for partial onset seizures. Zonisamide has not been associated with elevations in serum aminotransferase levels and clinically apparent drug induced liver disease has been reported with its use but is very rare. Zonisamide is a sulfonamide derivative with an anticonvulsant property. The exact mechanism of action remains to be elucidated. Zonisamide appears to block sodium and calcium channels, thereby stabilizing neuronal membranes and suppressing neuronal hyper-synchronization. Although zonisamide shows affinity for the gamma-aminobutyric acid (GABA)/benzodiazepine receptor ionophore complex, it does not potentiate the synaptic activity of GABA. In addition, this agent also facilitates both dopaminergic and serotonergic neurotransmission. Zonisamide is a sulfonamide anticonvulsant approved for use as an adjunctive therapy in adults with partial-onset seizures. Zonisamide may be a carbonic anhydrase inhibitor although this is not one of the primary mechanisms of action. 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. A benzisoxazole and sulfonamide derivative that acts as a CALCIUM CHANNEL blocker. It is used primarily as an adjunctive antiepileptic agent for the treatment of PARTIAL SEIZURES, with or without secondary generalization. Drug Indication Zonisamide capsules are indicated as adjunctive therapy in the treatment of partial seizures in adults with epilepsy. Zonisamide oral suspension is indicated as adjunctive therapy for the treatment of partial-onset seizures in adults and pediatric patients 16 years of age and older. FDA Label Monotherapy in the treatment of partial seizures, with or without secondary generalisation, in adults with newly diagnosed epilepsy; adjunctive therapy in the treatment of partial seizures, with or without secondary generalisation, in adults, adolescents, and children aged 6 years and above. Zonegran is indicated as: monotherapy in the treatment of partial seizures, with or without secondary generalisation, in adults with newly diagnosed epilepsy; adjunctive therapy in the treatment of partial seizures, with or without secondary generalisation, in adults, adolescents, and children aged six years and above. Mechanism of Action The mechanism of action by which zonisamide controls seizures has not been fully established. However, its antiepileptic properties may be due to its effects on sodium and calcium channels. Zonisamide blocks sodium channels and reduces voltage-dependent, transient inward currents, stabilizing neuronal membranes and suppressing neuronal hypersynchronization. It affects T-type calcium currents, but has no effect on L-type calcium currents. Zonisamide suppresses synaptically-driven electrical activity by altering the synthesis, release, and degradation of neurotransmitters, such as glutamate, gamma-aminobutyric acid (GABA), dopamine, serotonin (5-hydroxytryptamine [5-HT]), and acetylcholine. Furthermore, it binds to the GABA/benzodiazepine receptor ionophore complex without producing changes in chloride flux. _In vitro_ studies have suggested that zonisamide does not affect postsynaptic GABA or glutamate responses, nor the neuronal or glial uptake of [ 3 H]-GABA. The exact method by which zonisamide exerts its anticonvulsant effect is unknown. Some in vitro studies suggest a blockade of sodium channels, with consequent stabilization of neuronal membranes and suppression of neuronal hypersynchronization, whereas other in vitro studies have shown zonisamide to suppress synaptically-driven electrical activity without affecting postsynaptic GABA or glutamate responses. It appears then, that zonisamide dose not potentiate the synaptic activity of GABA. Zonisamide also serves as a weak inhibitor of carbonic anhydrase. Epileptiform discharges and behavioral seizures may be the consequences of excess excitation associated with the neurotransmitter glutamate, or from inadequate inhibitory effects associated with gamma-aminobutyric acid (GABA). Synaptic effects of these neurotransmitters are terminated by the action of transporter proteins that remove amino acids from the synaptic cleft. Excitation initiated by the synaptic release of glutamate is attenuated by the action of glial transporters glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1), and the neuronal transporter excitatory amino-acid carrier-1 (EAAC-1). GABA is removed from synaptic regions by the action of the transporters proteins GABA transporter-1 (GAT-1) and GABA transporter-3 (GAT-3). Albino rats with chronic, spontaneous recurrent seizures induced by the amygdalar injection of eCl3 were treated for 14 days with zonisamide (ZNS) (40 mg/kg, ip). Control animals underwent saline injection into the same amygdalar regions. Treatment control for both groups of intracerebrally injected animals was ip injection of equal volumes of saline. Western blotting was used to measure the quantity of glutamate and GABA transporters in hippocampus and frontal cortex. ZNS caused increase in the quantity of EAAC-1 protein in hippocampus and cortex and down regulation of the GABA transporter GAT-1. These changes occurred in both experimental and ZNS treated control animals. These data show that the molecular effect of ZNS, with up-regulation of EAAC-1 and decreased production of GABA transporters, should result in increased tissue and synaptic concentrations of GABA. Zonisamide is a broad-spectrum antiepileptic drug with multiple pharmacological activities [2][4] Its core mechanisms include: inhibiting carbonic anhydrase isozymes II and V to modulate ion balance and pH homeostasis; exerting anti-apoptotic effects in neuronal cells via upregulating MnSOD; regulating glutamate/GABA transporter expression to balance excitatory/inhibitory neurotransmission during epileptogenesis; and alleviating cardiac hypertrophy by increasing Hrd1 expression and suppressing ER stress [1][2][3][4] It is clinically indicated for the treatment of partial seizures and generalized seizures in adults and children [2] Beyond epilepsy, it shows potential therapeutic effects in neuronal protection and cardiac hypertrophy management through non-epileptic mechanisms [1][3] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (9.80 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 20.8 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. Solubility in Formulation 2: ≥ 2.08 mg/mL (9.80 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 20.8 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. Solubility in Formulation 3: ≥ 2.08 mg/mL (9.80 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 1 mg/mL (4.71 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C). (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.7119 mL | 23.5593 mL | 47.1187 mL | |
| 5 mM | 0.9424 mL | 4.7119 mL | 9.4237 mL | |
| 10 mM | 0.4712 mL | 2.3559 mL | 4.7119 mL |