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
Mean oral bioavailability is 97%.

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Metabolism / Metabolites
There is no evidence that miglustat is metabolized in humans.

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Biological Half-Life
The effective half-life of miglustat is approximately 6 to 7 hours.

Hepatotoxicity
In placebo controlled trials, liver test abnormalities were no more common with miglustat than with placebo treatment, and what abnormalities occurred were mild and resolved spontaneously usually without need for dose interruption. During these premarketing clinical trials and since its more widespread clinical availability, no instances of acute liver injury with jaundice have been reported attributable to miglustat. However, the total clinical experience with its use has been limited.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No published experience exists with miglustat during breastfeeding. Because of the lack of information and its side effect profile, most sources consider breastfeeding to be contraindicated during maternal miglustat therapy.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.
◈ What is miglustat?
Miglustat is a medication that has been used for treatment of mild to moderate Gaucher disease type 1. It has also been used to treat Niemann-Pick disease type C. Miglustat is sold under the brand name Zavesca®.People with Gaucher disease have low levels of an enzyme called glucocerebrosidase (gloo-co-se-ruh-BRO-si-dace). This enzyme helps break down fatty substances in the body. When this enzyme is missing or not working, fatty substances build up and can cause organ damage. Miglustat works in the body to limit the amount of the fatty substances being made. For more information, see the MotherToBaby fact sheet on Gaucher disease at https://mothertobaby.org/fact-sheets/gaucher-disease-pregnancy/.Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take this medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy.
◈ I take miglustat. Can it make it harder for me to get pregnant?
Studies have not been done in humans to see if miglustat could make it harder to get pregnant.
◈ Does taking miglustat increase the chance of miscarriage?
Miscarriage is common and can occur in any pregnancy for many different reasons. Studies have not been done in humans to see if miglustat could increase the chance for miscarriage. Studies in animals found a greater chance of pregnancy loss at doses around twice as much as would be used in human therapy.
◈ Does taking miglustat increase the chance of birth defects?
Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Studies have not been done in humans to see if miglustat increases the chance for birth defects. Animal studies done by the manufacturer did not find an increased chance of births defects.
◈ Does taking miglustat in pregnancy increase the chance of other pregnancy-related problems?
Studies have not been done in humans to see if miglustat increases the chance for pregnancy-related problems such as preterm delivery (birth before week 37) or low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth). Animal studies done by the manufacturer reported a higher chance of low birth weight.
◈ Does taking miglustat in pregnancy affect future behavior or learning for the child?
Studies have not been done in humans to see if miglustat causes cause long-term problems in behavior or learning.
◈ Breastfeeding while taking miglustat:
There are no studies looking at miglustat use while breastfeeding. The product label for miglustat states that because there is no data available, use during breastfeeding is not recommended. But, the benefit of using miglustat may outweigh possible risks. Your healthcare providers can talk with you about using miglustat and what treatment is best for you. Be sure to talk to your healthcare provider about all of your breastfeeding questions.
◈ If a male takes miglustat, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects?
In humans, one report did not find that miglustat use in 5 males affected the production of sperm or their fertility. Animal studies in rats found that miglustat exposure lowered sperm production, which lowered fertility. However, this was not found in all animal studies; and some animal strains are more sensitive to this exposure. In general, exposures that fathers or sperm donors have are unlikely to increase the risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures 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 mortality, weight loss, or obvious signs of toxicity (e.g., abnormal behavior, reduced activity) were observed in mice treated with miglustat (200 mg/kg per day for 6 days) compared to vehicle-treated mice [1]
In the NPC1⁻/⁻ mouse study: - miglustat treatment (50 mg/kg per day for 8 weeks) did not cause significant changes in liver function markers (alanine transaminase, ALT; aspartate transaminase, AST) or renal function markers (blood urea nitrogen, BUN; creatinine) compared to vehicle-treated NPC1⁻/⁻ mice (measured via 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
Miglustat, an N-alkylated imino sugar, is a synthetic analogue of D-glucose. Miglustat is an inhibitor of the enzyme glucosylceramide synthase, which is a glucosyl transferase enzyme responsible for catalyzing the formation of glucosylceramide (glucocerebroside). Glucosylceramide is a substrate for the endogenous glucocerebrosidase, an enzyme that is deficient in Gaucher's disease. The accumulation of glucosylceramide due to the absence of glucocerebrosidase results in the storage of this material in the lysosomes of tissue macrophages, leading to widespread pathology due to infiltration of lipid-engorged macrophages in the viscera, lymph nodes, and bone marrow. This results in secondary hematologic consequences including sever anemia and thrombocytopenia, in addition to the characteristic progressive hepatosplenomegaly, as well as skeletal complications including osteonecrosis and osteopenia with secondary pathological fractures.

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Miglustat exerts its biological effects primarily by inhibiting glucosylceramide synthase, which reduces the biosynthesis of glycosphingolipids—lipids that are abnormally accumulated in diseases like 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, while its ability to restore F508del-CFTR function addresses the underlying defect in ion transport [1]
In NPC disease, miglustat’s restoration of synaptic plasticity (LTP) and reduction of neuronal apoptosis suggest it may have neuroprotective effects, which could help slow 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.)