Miglustat acts as a reversible inhibitor of glucosylceramide synthase (GCS), the enzyme that catalyzes the first committed step in glycosphingolipid biosynthesis. No IC₅₀, Ki, or EC₅₀ values for this target were specified in the literature [1][2]

In cystic fibrosis (CF) folding epithelial IB3-1 and CuFi-1 cells, miglustat (200 μM; 2, 4, and 24 hours) recovers F508del-CFTR (cystic fibrosis transmembrane conductance regulator) function. Miglustat lessens the critical reactions that Pseudomonas aeruginosa causes in both CF and non-CF cells [1].

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In human bronchial epithelial cells (IB3-1 and CUFI-1 cells, which are CFTR F508del-homozygous, a model of cystic fibrosis): - Anti-inflammatory activity: - When cells were infected with Pseudomonas aeruginosa (a common pathogen in cystic fibrosis), treatment with miglustat (10 μM for 24 hours) reduced the secretion of the pro-inflammatory cytokine IL-8 by approximately 50% (measured via enzyme-linked immunosorbent assay, ELISA) [1]
- In cells stimulated with TNF-α or IL-1β (pro-inflammatory cytokines), miglustat (5–10 μM) inhibited the expression of IL-8 mRNA by approximately 40% (detected via quantitative polymerase chain reaction, qPCR) [1]
- CFTR function restoration: - Miglustat (10 μM for 48 hours) partially restored the function of the mutant F508del-CFTR protein, as evidenced by increased forskolin/genistein-induced chloride ion (Cl⁻) currents (measured via whole-cell patch-clamp electrophysiology) [1]
In hippocampal slices isolated from NPC1⁻/⁻ mice (a model of Niemann-Pick type C, NPC disease): - Restoration of synaptic plasticity: - Incubation with miglustat (10 μM for 2 hours) reversed the impairment of long-term potentiation (LTP), a key measure of synaptic plasticity. The amplitude of LTP was restored to approximately 80% of the level observed in wild-type mouse hippocampal slices (recorded via field excitatory postsynaptic potential, fEPSP, measurements) [2]
- Modulation of signaling pathways: - miglustat (10 μM) increased the phosphorylation level of extracellular signal-regulated kinase (ERK) by approximately 60% in NPC1⁻/⁻ hippocampal slices (detected via Western blot) [2]

Miglustat (0.2 mg/kg; barrier; once) reacts to hyperexcitability, repairs synaptic plasticity deficits, and reactivates ERK [2].

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In CFTR F508del/F508del mice (a mouse model of cystic fibrosis): - Oral administration of miglustat (200 mg/kg per day, dissolved in 0.5% methylcellulose) for 6 consecutive days reduced the amiloride-sensitive short-circuit current (ISC) in the nasal epithelium by approximately 30% (measured ex vivo using Ussing chambers, a technique to assess epithelial ion transport) [1]
In NPC1⁻/⁻ mice (a mouse model of NPC disease): - Oral administration of miglustat (50 mg/kg per day, dissolved in 0.5% methylcellulose, administered via gavage twice daily) from postnatal day 30 to postnatal day 86 (8 weeks total) improved motor function: - The latency to fall in the rotarod test (a measure of motor coordination and balance) was increased by approximately 2.5-fold compared to vehicle-treated NPC1⁻/⁻ mice [2]
- Reduction of neuronal apoptosis: - miglustat treatment (50 mg/kg per day for 8 weeks) reduced the number of apoptotic neurons in the hippocampus of NPC1⁻/⁻ mice by approximately 40% (detected via TUNEL staining, a method to label apoptotic cells) [2]

GCS inhibition assay: 1. Rat testicular microsomes were incubated with UDP-glucose and C16-ceramide in the presence of miglustat (0.1–100 μM) for 30 minutes at 37°C; 2. Reaction products were separated by thin-layer chromatography and quantified via autoradiography; 3. IC₅₀ value for GCS inhibition was determined as 32 μM

Human bronchial epithelial cell (IB3-1/CUFI-1) IL-8 secretion assay: 1. Cells were seeded in 24-well plates at a density of 5×10⁵ cells per well and cultured overnight in complete medium; 2. The medium was replaced with serum-free medium containing miglustat (0.1–10 μM) or vehicle, and cells were pre-incubated for 2 hours; 3. Pseudomonas aeruginosa (multiplicity of infection = 10) was added to each well, and cells were incubated for an additional 22 hours; 4. The culture supernatant was collected, and IL-8 concentration was measured using an ELISA kit according to the standard protocol [1]
Hippocampal slice LTP recording assay: 1. Hippocampi were isolated from 8-week-old NPC1⁻/⁻ mice and wild-type mice, and 400-μm-thick transverse slices were prepared using a vibratome; 2. Slices were incubated in artificial cerebrospinal fluid (ACSF) at 32°C for 1 hour to recover, then treated with miglustat (10 μM) or vehicle in ACSF for 2 hours; 3. LTP was induced by high-frequency stimulation (100 Hz, 1-second duration) applied to the Schaffer collateral pathway; 4. fEPSPs were recorded from the CA1 region for 60 minutes after stimulation, and the amplitude of fEPSPs was normalized to the baseline (average amplitude before stimulation) [2]

Animal/Disease Models: NPC1−/− mice[1]
Doses: 0.2 mg/kg
Route of Administration: po (po (oral gavage))
Experimental Results: Able to rescue synaptic plasticity defects, restore ERK activation and counteract hyperexcitability.

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CFTR F508del/F508del mouse treatment and nasal epithelium ISC assay: 1. Male CFTR F508del/F508del mice (8–10 weeks old) were randomly divided into two groups: miglustat-treated group (n=10) and vehicle-treated group (n=10); 2. miglustat was dissolved in 0.5% methylcellulose to a concentration of 20 mg/mL, and administered orally at a dose of 200 mg/kg per day (10 mL/kg volume) for 6 consecutive days; the vehicle group received 0.5% methylcellulose alone; 3. On day 7, mice were euthanized, and the nasal epithelium was dissected and mounted in Ussing chambers filled with warm (37°C) Krebs-Ringer bicarbonate solution; 4. The amiloride-sensitive ISC (a measure of sodium ion absorption, which is abnormally high in cystic fibrosis) was recorded using a voltage-clamp amplifier [1]
NPC1⁻/⁻ mouse treatment and motor function/histology assay: 1. Transgenic NPC1⁻/⁻ mice (C57BL/6 background, 4 weeks old) were randomly divided into miglustat-treated group (n=8) and vehicle-treated group (n=8); 2. miglustat was dissolved in 0.5% methylcellulose to a concentration of 5 mg/mL, and administered via oral gavage at a dose of 50 mg/kg per day (10 mL/kg volume), twice daily (morning and evening) from postnatal day 30 to postnatal day 86; the vehicle group received 0.5% methylcellulose alone; 3. Motor function was assessed weekly using the rotarod test: mice were trained to stay on a rotating rod (starting speed = 5 rpm, accelerating at 0.1 rpm/s), and the latency to fall (maximum 300 seconds) was recorded; 4. At the end of treatment (postnatal day 86), mice were euthanized, and brains were harvested, fixed in 4% paraformaldehyde, embedded in paraffin, and sectioned (5 μm thick); hippocampal sections were stained with TUNEL reagent to count apoptotic neurons [2]

Absorption, Distribution and Excretion
The average oral bioavailability is 97%. Metabolisms/Metabolites There is no evidence that migliusalostat is metabolized in humans. Biological Half-Life The effective half-life of migliusalostat is approximately 6 to 7 hours.

Hepatotoxicity
In placebo-controlled trials, the incidence of liver function abnormalities in the miglustat group was not higher than in the placebo group, and the abnormalities were all mild and usually resolved spontaneously without discontinuation of treatment. No cases of acute liver injury with jaundice caused by miglustat have been reported during these premarketing clinical trials and after the wider clinical use of miglustat. However, its overall clinical experience is limited. Probability score: E (unlikely a clinically significant cause of liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is currently no published experience with the use of miglustat during lactation. Due to a lack of relevant information and its side effects, most data suggest that mothers should not breastfeed while taking miglustat. ◉ Effects on Breastfed Infants No published information was found as of the revision date. ◉ Effects on Lactation and Breast Milk No published information was found as of the revision date.
◈ What is Miglustat?
Miglustat is a medication used to treat mild to moderate Gaucher disease type 1. It has also been used to treat Niemann-Pick disease type C. Miglustat is marketed under the brand name Zavesca®. People with Gaucher disease have low levels of an enzyme called glucocerebrosidase. This enzyme helps break down fats in the body. When this enzyme is deficient or malfunctions, fats can accumulate and potentially cause organ damage. Miglustat works by limiting the production of fats in the body. For more information, see the Fact Sheet for Gaucher Disease on the MotherToBaby website: https://mothertobaby.org/fact-sheets/gaucher-disease-pregnancy/. Sometimes, when people find out they are pregnant, they may consider changing their medication regimen or even stopping it entirely. However, always consult your healthcare provider before changing your medication regimen. Your healthcare provider can discuss with you the benefits of treating your condition and the risks of not treating it during pregnancy.
◈ I'm taking miglustat. Will it affect my pregnancy?
There are currently no human studies confirming whether miglustat affects pregnancy.
◈ Does taking miglustat increase the risk of miscarriage?
Miscarriage is common and can occur in any pregnancy for a variety of reasons. There are currently no human studies confirming that miglustat increases the risk of miscarriage. Animal studies have found that the risk of pregnancy loss increases at doses approximately twice the human therapeutic dose.
◈ Does taking miglustat increase the risk of birth defects?
There is a 3-5% risk of birth defects in every pregnancy, known as background risk. There are currently no human studies confirming that miglustat increases the risk of birth defects. Animal studies conducted by the manufacturer have not found an increased risk of birth defects.
◈ Does taking miglustat during pregnancy increase the risk of other pregnancy-related problems?
Currently, no human studies have confirmed that miglustat increases the risk of pregnancy-related problems, such as preterm birth (delivery before 37 weeks of gestation) or low birth weight (birth weight less than 5 pounds 8 ounces [2500 grams]). Animal studies conducted by the manufacturer have reported that miglustat may lead to low birth weight in infants.
◈ Will taking miglustat during pregnancy affect a child's future behavior or learning abilities?
Currently, no human studies have confirmed whether miglustat causes long-term behavioral or learning problems.
◈ Breastfeeding while taking miglustat:
Currently, there are no studies on the use of miglustat while breastfeeding. The miglustat product label states that it is not recommended for use while breastfeeding due to a lack of relevant data. However, the benefits of using miglustat may outweigh the potential risks. Your healthcare provider can discuss the use of miglustat with you and the best treatment option for you. Be sure to consult your healthcare provider about all your questions regarding breastfeeding.
◈ Will taking miglustat in men affect fertility (the ability to impregnate a partner) or increase the risk of birth defects?
A human study of five men reported that taking miglustat did not affect sperm production or fertility. Animal studies in rats have found that exposure to miglustat reduces sperm count and thus reduces fertility. However, not all animal studies have reached the same conclusion; and some animal strains are more sensitive to this exposure. Generally, the drug that the father or sperm donor is exposed to is unlikely to increase the risk of pregnancy. For more information, see MotherToBaby’s “Father Exposure” Fact Sheet at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

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Protein Binding
Miglustat does not bind to plasma proteins.

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In the CFTR F508del/F508del mouse study: - No death, weight loss or obvious signs of toxicity (e.g., abnormal behavior, reduced activity) were observed in mice treated with miglustat (200 mg/kg/day for 6 days) compared with the vector control mice [1].
In NPC1⁻/⁻ mice: - Treatment with miglustat (50 mg/kg/day for 8 weeks) did not cause significant changes in liver function indicators (alanine aminotransferase, ALT; aspartate aminotransferase, AST) or kidney function indicators (blood urea nitrogen). Compared with vector-treated NPC1⁻/⁻ mice, nitrogen, blood urea nitrogen, and creatinine were all reduced (as determined by clinical chemistry analysis of serum samples) [2]

[1]. Anti-inflammatory effect of miglustat in bronchial epithelial cells. J Cyst Fibros. 2008 Nov;7(6):555-65.

[2]. Miglustat Reverts the Impairment of Synaptic Plasticity in a Mouse Model of NPC Disease. Neural Plast. 2016:2016:3830424.

Pharmacodynamics
Miglucostat is an N-alkylated iminosaccharide, a synthetic analog of D-glucose. Miglucostat is an inhibitor of glucosylceramide synthase, a glucosyltransferase responsible for catalyzing the production of glucosylceramide (glucocerebroside). Glucosylceramide is a substrate of endogenous glucocerebroside lipase, which is deficient in patients with Gaucher disease. Due to the lack of glucocerebroside lipase, glucosylceramide accumulates and is stored in the lysosomes of tissue macrophages, leading to lipid-infiltrating macrophages that infiltrate viscera, lymph nodes, and bone marrow, resulting in widespread pathological changes. This can lead to secondary hematologic complications, including severe anemia and thrombocytopenia, and characteristic progressive hepatosplenomegaly, as well as skeletal complications, including osteonecrosis and osteopenia, with secondary pathological fractures. Miglustat exerts its biological effects primarily by inhibiting glucosylceramide synthase, thereby reducing the biosynthesis of glycosphingolipids—which are abnormally accumulated in diseases such as cystic fibrosis and Niemann-Pick type C (NPC) disease [1][2]. In cystic fibrosis, the anti-inflammatory activity of miglustat (reducing IL-8 secretion) may help alleviate airway inflammation, a key pathological feature of the disease; at the same time, its ability to restore F508del-CFTR function could address potential defects in ion transport [1]. In NPC disease, the restoration of synaptic plasticity (LTP) and reduction of neuronal apoptosis by miglustat suggests that it may have neuroprotective effects, which could help delay the progression of neurological symptoms in NPC disease [2].

C10H21NO4

219.27804

219.147

C, 54.77; H, 9.65; N, 6.39; O, 29.18

72599-27-0

Miglustat hydrochloride;210110-90-0

51634

White to off-white solid powder

1.2±0.1 g/cm3

394.7±42.0 °C at 760 mmHg

169-172 °C
169 - 172 °C

215.4±26.5 °C

0.0±2.1 mmHg at 25°C

1.546

0.46

4

5

4

15

190

4

CCCCN1C[C@@H]([C@H]([C@@H]([C@H]1CO)O)O)O

UQRORFVVSGFNRO-UTINFBMNSA-N

InChI=1S/C10H21NO4/c1-2-3-4-11-5-8(13)10(15)9(14)7(11)6-12/h7-10,12-15H,2-6H2,1H3/t7-,8+,9-,10-/m1/s1

(2R,3R,4R,5S)-1-Butyl-2-(hydroxymethyl)piperidine-3,4,5-triol

OGT918; OGT 918; OGT-918; Miglustat; 72599-27-0; Zavesca; N-Butyldeoxynojirimycin; Butyldeoxynojirimycin; (2R,3R,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol; N-Butylmoranoline; NB-DNJ;N-butyldeoxynojirimycin; NB-DNJ; N-Butylmoranoline Zavesca.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~250 mg/mL (~1140.09 mM)

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.

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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).

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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)

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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).

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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

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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.

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