- Tizanidine (BRN 0618691; AB 021) exerts pharmacological effects by targeting central α2-adrenergic receptors; the Ki value for binding to α2-adrenergic receptors is approximately 2.6 nM [1]

- In patients with spasticity secondary to multiple sclerosis (MS): Tizanidine (BRN 0618691; AB 021) was administered orally at doses of 4–8 mg/day (divided into 3–4 doses). After 4 weeks of treatment, the Ashworth Scale score (a measure of spasticity severity) decreased by 20%–35% compared to the baseline. Patients reported significant improvements in muscle stiffness and difficulty in movement, with a response rate (≥20% reduction in Ashworth score) of 65%–75% [1]
- In patients with spasticity secondary to stroke: Tizanidine (BRN 0618691; AB 021) was given orally at doses of 6–12 mg/day (divided into 3–4 doses). After 6 weeks of treatment, the Ashworth Scale score decreased by 18%–30% compared to the baseline. Additionally, the Functional Independence Measure (FIM) score (assessing daily living abilities) increased by 15%–25%, indicating improved functional mobility [1]
- In patients with spasticity secondary to spinal cord injury (SCI): Tizanidine (BRN 0618691; AB 021) was administered orally at doses of 8–16 mg/day (divided into 3–4 doses). After 8 weeks of treatment, the Ashworth Scale score decreased by 25%–40% compared to the baseline. The number of painful muscle spasms per day was reduced by 30%–50%, and sleep quality was improved in 55%–65% of patients [1]

Absorption, Distribution and Excretion
This drug undergoes significant first-pass metabolism. After oral administration, tizanidine is largely absorbed. The absolute oral bioavailability of tizanidine is approximately 40%. Effect of Food on Absorption: Food can increase the absorption rate of both tablets and capsules. The increase in absorption rate for tablets (approximately 30%) is significantly greater than that for capsules (approximately 10%). When capsules and tablets are taken with food, the absorption of capsules is approximately 80% of that of tablets. Therefore, it is recommended to take them with food to improve absorption, especially tablets. This drug is primarily excreted via the kidneys. It is widely distributed throughout the body. The mean steady-state volume of distribution is 2.4 L/kg. Precautions Regarding Renal Impairment: Compared to healthy elderly individuals, elderly patients with renal insufficiency (creatinine clearance < 25 mL/min) have a clearance rate that is more than 50% lower; this is expected to lead to a prolonged duration of clinical efficacy. This drug should be used with caution in patients with renal impairment.

---

Metabolism/Metabolites
Approximately 95% of the ingested dose of tizanidine is metabolized. The main enzyme involved in the hepatic metabolism of tizanidine is CYP1A2.
Known metabolites of tizanidine include 2-[(5-chloro-2,1,3-benzothiadiazol-4-yl)amino]-4,5-dihydro-1H-imidazol-4-ol.
Elimination pathway: Approximately 95% of the administered dose is metabolized.
Half-life: 2.5 hours

---

Biological half-life
Approximately 2.5 hours.

---

- Absorption: Orally administered tizanidine (BRN 0618691; AB 021) is rapidly absorbed, reaching peak plasma concentration (Cmax) within 1–2 hours after administration. Oral bioavailability is 34%–40%, unaffected by food intake [1]
- Distribution: The volume of distribution (Vd) of tizanidine (BRN 0618691; AB 021) is 2.4–4.0 L/kg. It can cross the blood-brain barrier, with a brain-to-plasma concentration ratio of approximately 0.8–1.2 [1]
- Metabolism: Tizanidine (BRN 0618691; AB 021) is mainly metabolized in the liver via cytochrome P450 1A2 (CYP1A2). The main metabolite is an inactive glucuronide conjugate, accounting for 60%–70% of the total metabolites [1]
- Excretion: Tizanidine (BRN 0618691; AB 021) is mainly excreted via the kidneys. Approximately 60%–70% of the administered dose is excreted in the urine as metabolites and 20%–30% in the feces. The elimination half-life (t1/2) in healthy adults is 2.5–4 hours [1]
- Plasma protein binding: The plasma protein binding of tizanidine (BRN 0618691; AB 021) is 30%–40% [1]

Toxicity Summary
Tizanidine reduces spasms by activating α2-adrenergic receptor sites, enhancing presynaptic inhibition of motor neurons. Hepatotoxicity
Approximately 5% of patients taking tizanidine experience a transient, asymptomatic increase in serum ALT exceeding three times the upper limit of normal, compared to only 0.4% in the placebo group. Reports of severe hepatotoxicity, acute liver failure, and death have been mentioned in review articles on tizanidine, but published case reports are scarce. In these case reports, the incubation period for jaundice was 2 to 14 weeks, and enzyme elevations were cholestatic and hepatocellular (Case 1). No immune hypersensitivity or autoimmune features were mentioned. Complete recovery occurred within 1 to 2 months. Probability Score: C (Possibly a rare cause of clinically significant liver injury). Protein Binding Approximately 30% is bound to plasma proteins.

---

- Common adverse reactions: Oral tizanidine (BRN 0618691; AB 021) (4-16 mg/day) is associated with mild to moderate adverse reactions, including somnolence (incidence: 25%-35%), dry mouth (15%-25%), dizziness (10%-20%), and fatigue (8%-15%). These adverse reactions are usually dose-related and will decrease with continued treatment or dose reduction [1]
- Hepatotoxicity: Transient elevations of liver enzymes (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) occur in 5% to 10% of patients receiving tizanidine (BRN 0618691; AB 021) treatment for more than 8 weeks. This increase is usually mild (2 to 3 times the upper limit of normal) and is reversible upon dose reduction or discontinuation [1]
- Drug Interactions:Tizanidine (BRN 0618691; AB 021) when used in combination with CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin) significantly increases plasma concentrations (3 to 5 times), thereby increasing the risk of severe drowsiness, hypotension, and bradycardia. Therefore, it is generally not recommended to use these drugs concurrently [1]

[1]. A practical overview of tizanidine use for spasticity secondary to multiple sclerosis, stroke, and spinal cord injury. Curr Med Res Opin. 2008 Feb;24(2):425-39.

Tizanidine is a 2,1,3-benzothiadiazole with its C-4 position substituted by Δ(1)-imidazoline-2-ylamino and chlorine, respectively. It is an α2-adrenergic receptor agonist, exhibiting dual action as an α-adrenergic agonist and muscle relaxant. It belongs to the benzothiadiazole class of compounds, which is also a member of the imidazole class. Tizanidine is a fast-acting drug used to treat muscle spasms, which can be caused by multiple sclerosis, stroke, acquired brain injury, or spinal cord injury, or by musculoskeletal injury. Regardless of the cause, muscle spasms can be an extremely painful and debilitating condition. Tizanidine was initially approved by the FDA in 1996. It is an α2-adrenergic receptor agonist that reduces spasms by presynaptic inhibition of excitatory neurotransmitters that cause neuronal firing, thereby promoting muscle spasms. Tizanidine is a centrally acting α2-adrenergic agonist. Tizanidine's mechanism of action is as an α2-adrenergic agonist. Tizanidine is a commonly used muscle relaxant, but it has been reported to be associated with rare cases of acute liver injury, some of which have even led to death. Tizanidine is a short-acting drug used to treat spasticity. It is an α2-adrenergic receptor agonist and is presumably used to relieve spasticity by enhancing presynaptic inhibition of motor neurons. In animal models, tizanidine has no direct effect on skeletal muscle fibers or neuromuscular junctions, nor does it significantly affect monosynaptic spinal reflexes. Tizanidine's effects are most pronounced on polysynaptic pathways. The overall effect of these effects is thought to reduce facilitation of spinal motor neurons. See also: Tizanidine hydrochloride (salt form).

---

Drug Indications
Tizanidine is indicated for the relief of muscle spasms that affect daily life. Due to the short duration of action of tizanidine, it is generally recommended to use it only when there is a specific need for symptom relief.
FDA Label
Mechanism of Action
Tizanidine relieves spasticity by stimulating α2-adrenergic receptor sites, causing presynaptic inhibition of motor neurons. This drug acts on the central nervous system, reducing the release of excitatory amino acids such as glutamate and aspartate, which induce neuronal firing and subsequently muscle spasms. This reduction in the release of these excitatory neurotransmitters ultimately leads to presynaptic inhibition of motor neurons. Tizanidine's most potent effects have been shown to occur in multisynaptic pathways of the spinal cord. Tizanidine's analgesic and anticonvulsant activity may also be attributed to its agonistic effect on α2 receptors. Tizanidine has a weak affinity for α1 receptors, which explains its mild and transient effects on the cardiovascular system.
Pharmacodynamics
About Spasticity
Spasticity is defined as increased muscle activity accompanied by uncontrolled, repetitive, involuntary contractions of skeletal muscles. Patients with muscle spasticity may experience limited mobility, severe pain, decreased quality of life, and difficulty performing personal hygiene and care activities. Tizanidine is a fast-acting medication used to relieve muscle spasms required for specific activities. As an agonist of α2-adrenergic receptors, it relieves muscle spasm symptoms, allowing patients to continue normal daily activities. In animal models, tizanidine has not shown direct effects on skeletal muscle fibers or neuromuscular junctions, nor has it shown significant effects on monosynaptic spinal reflexes (consisting of communication between only one sensory neuron and one motor neuron). Tizanidine reduces the frequency of muscle spasms and clonus. Tizanidine has a stronger effect on polysynaptic reflexes, which involve communication between multiple interneurons (relay neurons) and the motor neurons stimulating muscle movement. Effects on blood pressure and heart rate: This drug can lower heart rate and blood pressure in humans. However, abrupt discontinuation of tizanidine may result in rebound hypertension and tachycardia, as well as worsening of spasms.

---

- Tizanidine (BRN 0618691; AB 021) is a centrally acting α2-adrenergic receptor agonist used clinically to treat spasticity caused by multiple sclerosis, stroke and spinal cord injury. Its mechanism of action involves activating presynaptic α2-adrenergic receptors in the spinal cord, thereby inhibiting the release of norepinephrine and other excitatory neurotransmitters, thereby reducing the activation of spinal motor neurons and relieving spasticity[1]
- Dosage adjustment: For patients with mild to moderate hepatic impairment (Child-Pugh A or B), the initial dose of Tizanidine (BRN 0618691; AB 021) should be reduced to 2 mg/day (divided into 2 doses), and the maximum daily dose should not exceed 8 mg. For patients with severe hepatic impairment (Child-Pugh C), this product is not recommended due to the risk of elevated plasma drug concentrations[1].
- Withdrawal reaction: Abrupt discontinuation of tizanidine (BRN 0618691; AB 021) may cause rebound spasms, anxiety, tachycardia and hypertension. Therefore, the dose should be gradually reduced over 7-14 days when discontinuing the drug[1].

C9H8N5SCL

253.71132

253.019

51322-75-9

Tizanidine hydrochloride;64461-82-1;Tizanidine-d4;1188331-19-2

5487

Light yellow to yellow solid powder

1.82 g/cm3

391.2ºC at 760 mmHg

221 - 223ºC

190.4ºC

1.553

2

4

2

16

300

0

XFYDIVBRZNQMJC-UHFFFAOYSA-N

InChI=1S/C9H8ClN5S/c10-5-1-2-6-8(15-16-14-6)7(5)13-9-11-3-4-12-9/h1-2H,3-4H2,(H2,11,12,13)

5-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-2,1,3-benzothiadiazol-4-amine

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

---

Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

View More

Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

---

Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

View More

Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

---

Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

---

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