Aminoglycoside antibiotic; DNase I (IC50 = 0.57 mM)

Gentamicin is nontoxic to tissue culture monolayers, does not inhibit viral replication, and is a more potent in vitro bacterial inhibitor than the combination of penicillin and streptomycin [2]. Gentamicin is more effective than penicillin and streptomycin against a wider range of organisms (Pseudomonas aeruginosa, Proteus spp., and Streptococcus) and has been successfully added as an additive in commercial mycological media to inhibit bacterial growth [2]. Gentamicin is stable at autoclaving temperatures, nontoxic to rhesus kidney, HeLa, and human amnion cells, and does not interfere with the cytopathic effects of some polioviruses and echoviruses in tissue culture [2]. Several species in the genus Micromonospora produce gentamicin [3]. The major groove of the RNA A site is where gentamicin C1a binds [3].

It has been demonstrated that gentamicin, both oral and injectable, has strong antibacterial activity against Y. pestis in infection models using mice [3]. Mice treated with gentamicin (0.27 g/kg) demonstrated a substantial decrease in bacteria on foreign bodies [4].

Absorption, Distribution and Excretion
Gentamicin is primarily excreted via the kidneys. In patients with normal renal function, 70% or more of the initial gentamicin dose is excreted in the urine within 24 hours. Gentamicin excretion is significantly reduced in patients with renal insufficiency. The renal clearance of gentamicin is comparable to the individual's creatinine clearance. Following intramuscular injection, gentamicin is distributed into breast milk. After intramuscular or intravenous injection, gentamicin is distributed in low concentrations into the cerebrospinal fluid (CSF). Following intrathecal injection, the concentration of gentamicin in the CSF depends on the dose, injection site, volume of dose dilution, and the presence of CSF flow obstruction. Concentrations achieved may vary significantly between patients. One study showed that after intrathecal injection of 4 mg gentamicin, the CSF concentration remained between 19 and 46 μg/mL for 8 hours, decreasing to below 3 μg/mL after 20 hours. Gentamicin can cross the placental barrier.
After parenteral administration of standard doses of gentamicin, the drug can be detected in lymph, subcutaneous tissue, lungs, sputum, and bronchial fluid, pleural fluid, pericardial fluid, synovial fluid, ascites, and peritoneal fluid. Drug concentrations in bile may be low, suggesting minimal bile excretion. In patients with ventilator-associated pneumonia treated with intravenous gentamicin (240 mg once daily), the drug concentration in alveolar lining fluid was 32% of the serum concentration 2 hours after administration, with a mean concentration of 4.24 μg/mL. Only very low concentrations of gentamicin are achieved in ocular tissues after intramuscular or intravenous injection.
Gentamicin accumulation does not appear to occur in patients with normal renal function receiving a dose of 1 mg/kg every 8 hours for 7–10 days. However, accumulation may occur at higher doses and/or prolonged administration, particularly in patients with renal impairment.
For more complete data on absorption, distribution, and excretion of gentamicin (18 items in total), please visit the HSDB record page.
Metabolism/Metabolites
Gentamicin is hardly metabolized.
Gentamicin is not metabolized. Gentamicin is primarily excreted unchanged via glomerular filtration.
Biological Half-Life
A study evaluating the pharmacokinetics of gentamicin in children and adults reported an average half-life of 75 minutes after intravenous injection. The average half-life after intramuscular injection is approximately 29 minutes longer. Fever and anemia may shorten the half-life, but usually no dose adjustment is required. Severe burns can also shorten the half-life and may lead to decreased serum gentamicin concentrations.
In adults with normal renal function, the plasma elimination half-life of gentamicin is typically 2–4 hours; while in adults with severely impaired renal function, the plasma elimination half-life has been reported to be 24–60 hours. The serum half-life of gentamicin is an average of 3–3.5 hours in infants aged 1 week to 6 months, and 5.5 hours in full-term infants and older preterm infants less than 1 week old. In smaller premature infants, the plasma half-life is approximately 5 hours for infants weighing over 2 kg, approximately 8 hours for infants weighing 1.5–2 kg, and approximately 11.5 hours for infants weighing less than 1.5 kg. …It has been reported that in adults with normal renal function, the terminal elimination half-life exceeds 100 hours after repeated intramuscular or intravenous injections of this drug.

Toxicity Summary
Identification and Uses: Gentamicin sulfate is an aminoglycoside antibiotic. Gentamicin is widely used to treat serious infections. It is effective against a variety of Gram-negative bacteria and Staphylococcus aureus. It is ineffective against anaerobic bacteria and has weak activity against hemolytic streptococci and pneumococci. Human Exposure and Toxicity: Main Risks and Target Organs: The main toxic effects are vestibular damage, deafness, and renal impairment. Damage to the vestibular portion of the eighth cranial nerve appears to be more severe than damage to the cochlear portion. The main target organs are the eighth cranial nerve and the kidneys. Damage to the eighth cranial nerve (including two branches) can lead to tinnitus, deafness, nausea, vomiting, vertigo, dizziness, and nystagmus, and cause nephrotoxicity, leading to acute tubular necrosis and ultimately renal failure. Hearing loss, dizziness, vertigo, ataxia, nausea, vomiting, and renal impairment in patients treated with gentamicin suggest gentamicin poisoning. Other toxic manifestations include muscle paralysis and respiratory depression. Gentamicin accumulates in the renal cortex, and when the concentration reaches a critical level, the kidney's concentrating function is impaired. Nephrotoxicity appears to be associated with the duration of trough serum concentrations exceeding 2 μg/ml. Its exact mechanism of toxicity is unclear. Ototoxicity and vestibular toxicity appear to be closely associated with elevated peak gentamicin concentrations (greater than 10 μg/ml). Gentamicin accumulates in the endolymph and perilymph, leading to progressive damage to ventricular and cochlear cells. Repeated use of gentamicin may result in progressive cell damage, eventually causing deafness. Gentamicin appears to cause greater damage to the vestibular system than to the cochlea. In rare cases, neuromuscular blockade may occur, accompanied by acute muscle paralysis and respiratory arrest. Most cases occur during anesthesia or with other neuromuscular blocking agents, but can also occur after intrapleural or intraperitoneal infusion of high doses of gentamicin or other aminoglycoside antibiotics. This can also occur after intravenous or intramuscular injection. Animal studies: Clinical signs of poisoning in rodents include convulsions, collapse, decreased activity, polydipsia, dyspnea, and ataxia. Dogs exhibited muscle tremors, drooling, and anorexia. Histopathological examination of the kidneys of dogs that died within 13 days of administration revealed proximal tubular necrosis. Three female rhesus monkeys were randomly divided into three groups and administered gentamicin aqueous solution intramuscularly at doses of 0, 6, or 30 mg/kg body weight/day for 3 weeks. Adverse clinical symptoms were limited to the 30 mg/kg body weight/day group, including marked pallor and ptosis, significant balance disturbances from day 20, and decreased food intake and weight gain from week 2. Electron microscopy of the renal tubules in the 30 mg/kg body weight/day group revealed the presence of myeloid bodies in the tubular cells and lumen, increased phagocytoses, loss of the brush border, and epithelial cell detachment from the basement membrane. Beagles (n=4 per group, half male and half female) were orally administered gentamicin capsules at doses of 0, 2, 10, or 60 mg/kg body weight/day for 14 weeks. Occasionally, vomiting and diarrhea were observed in the treatment groups. Autopsy results showed that two animals in the high-dose group developed interstitial nephritis. Gentamicin had a negative impact on rat sperm parameters and testicular cell apoptosis. In two generations of rat studies, no treatment-related changes were found in pregnancy rate, litter size and weight, prenatal mortality, or fetal malformations. In vitro studies examined the ability of gentamicin to induce positive gene mutations in Chinese hamster ovarian cells at concentrations of 128–5000 μg/mL, and its ability to induce chromosomal aberrations in these cells at concentrations of 800–5000 μg/mL, regardless of metabolic activation. The drug was also tested in vivo to evaluate its ability to induce nuclear abnormalities in mouse bone marrow cells at intravenous doses of 20–80 mg/kg body weight (the highest dose being the maximum tolerated dose). No mutagenic activity was found.

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Hepatotoxicity
Intravenous and intramuscular gentamicin were associated with a mild (asymptomatic) increase in serum alkaline phosphatase levels, but rarely affected aminotransferase or bilirubin levels, and these changes rapidly subsided upon discontinuation of gentamicin. Only sporadic case reports have shown that treatment with aminoglycosides, including gentamicin, can cause acute liver injury with jaundice, but evidence is insufficient in most cases. The liver injuries described in these reports are usually mixed, but can also develop into cholestatic hepatitis. The incubation period is short, usually within 1 to 3 weeks, and is typically accompanied by rash, fever, and sometimes eosinophilia. Recovery usually occurs within 1 to 2 months, and there are no reports of chronic injury. Aminoglycosides have not been included or mentioned in large case series of drug-induced liver disease and acute liver failure; therefore, gentamicin-induced liver injury, if it occurs, is extremely rare. Probability score: E (unlikely to be the cause of clinically apparent liver injury). Effects during pregnancy and lactation: ◉ Overview of medication use during lactation: Gentamicin is rarely excreted into breast milk. Neonates appear to absorb small amounts of gentamicin, but even with three-times-daily dosing, serum concentrations are far lower than those achieved when treating neonatal infections, making systemic effects of gentamicin unlikely. Older infants are expected to absorb even less gentamicin. Because the concentration of gentamicin in breast milk fluctuates very little with multiple-dose regimens, adjusting the timing of breastfeeding and administration offers little benefit in reducing infant exposure. Data on single-dose regimens are currently unavailable. Monitoring for potential effects on the infant's gut microbiota, such as diarrhea, candidiasis (e.g., thrush, diaper rash), or rare hematochezia (suggesting possible antibiotic-associated colitis), should be conducted.
The risk to breastfed infants is minimal or nonexistent for mothers using ear or eye drops containing gentamicin.
◉ Effects on Breastfed Infants
A 5-day-old infant presented with hematochezia, possibly due to the mother's concurrent use of clindamycin and gentamicin.
A 2-month-old infant had been exclusively breastfed since birth. His mother had taken several medications during pregnancy, but could not recall the specific names. She developed mastitis and was treated with amoxicillin-clavulanate potassium 1g orally every 12 hours and gentamicin 160mg intramuscularly once daily. The infant began breastfeeding for 10 minutes 15 minutes after the first dose of both medications. Approximately 20 minutes later, the infant developed generalized urticaria, which subsided after 30 minutes. Several hours later, the infant was breastfed again, and the urticaria recurred after 15 minutes, subsiding after an hour. After switching to formula feeding and avoiding further penicillin exposure, the infant was followed up until 16 months of age without recurrence of the reaction. This adverse reaction was most likely caused by the antibiotic in the breast milk. The causative drug could not be identified, but amoxicillin-clavulanate potassium was the most likely culprit.
◉ Effects on Lactation and Breast Milk
As of the revision date, no relevant published information was found.

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Protein Binding
Studies have shown that the plasma protein binding rate of gentamicin is between 0-30%, depending on the detection method.

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Interactions
An in vitro study showed that cytarabine may antagonize the activity of gentamicin against Klebsiella pneumoniae.
In in vitro and in vivo studies in patients with renal failure, gentamicin appeared to be more readily inactivated by anti-pseudomonal penicillins (e.g., ticarcillin) than amikacin.
Concurrent and/or sequential use of aminoglycosides and other systemic, oral, or topical medications with neurotoxicity, ototoxicity, or nephrotoxicity. Concomitant use of aminoglycosides with other drugs (e.g., other aminoglycosides, acyclovir, amphotericin B, bacitracin, capreomycin, certain cephalosporins, colistin, cisplatin, methoxyflurane, polymyxin B, vancomycin) may result in additive toxicity and should be avoided whenever possible. /Aminoglycosides/
Because the risk of ototoxicity may increase due to additive effects or changes in serum and tissue concentrations of aminoglycosides when used in combination with other drugs, aminoglycosides should not be used in combination with potent diuretics (e.g., ethacrynic acid, furosemide, urea, or mannitol). Studies have shown that concomitant use of certain antiemetics that suppress vestibular nausea and vomiting and vertigo (e.g., diphenhydramine, meclomethasone) may mask the symptoms of aminoglycoside-related vestibular ototoxicity. /Aminoglycosides/
For more complete data on interactions with gentamicin (12 items in total), please visit the HSDB record page.

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Non-human toxicity values
Mouse intramuscular LD50: 167 mg/kg
Mouse intravenous LD50: 51 mg/kg
Mouse subcutaneous LD50: 274 mg/kg
Mouse intraperitoneal LD50: 235 mg/kg
For more complete data on non-human toxicity values of gentamicin (out of 8), please visit the HSDB record page.

[1]. A rapid and sensitive method for kinetic study and activity assay of DNase I in vitro based on a GO-quenched hairpin probe. Anal Bioanal Chem. 2016 May;408(14):3801-9.

[2]. Antibacterial activity of gentamicin sulfate in tissue culture. Appl Microbiol. 1970 Dec;20(6):989-90.

[3]. Microbial biosynthesis and applications of gentamicin: a critical appraisal. Crit Rev Biotechnol. 2008;28(3):173-212.

[4]. Effect of treatment with methicillin and gentamicin in a new experimental mouse model of foreignbody infection. Antimicrob Agents Chemother. 1994 Sep;38(9):2047-53.

Therapeutic Uses
Antimicrobial Agent; Protein Synthesis Inhibitor
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that lists human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes summary information about the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure being investigated); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (for providing patient health information) and PubMed (for providing citations and abstracts of academic articles in the medical field). Gentamicin is included in the database. Gentamicin injection is indicated for the treatment of serious infections caused by the following susceptible strains: Pseudomonas aeruginosa, Proteus spp. (indole-positive and indole-negative), Escherichia coli, Klebsiella pneumoniae-Enterobacter-Serratia spp., Citrobacter spp., and Staphylococcus spp. (coagulase-positive and coagulase-negative). /US product label contains/ Gentamicin, when used in combination with carbenicillin, is effective in treating life-threatening infections caused by Pseudomonas aeruginosa. Additionally, gentamicin, when used in combination with penicillin antibiotics, is effective in treating infective endocarditis caused by group D streptococci. /US product label contains/ For more complete data on the therapeutic uses of gentamicin (26 types), please visit the HSDB record page.

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Drug Warning
/Black Box Warning/ Because aminoglycosides can be toxic, patients receiving this type of medication should be closely monitored clinically. Like other aminoglycosides, gentamicin for injection has potential nephrotoxicity. Patients with impaired renal function and those receiving high doses or long-term treatment are at higher risk of nephrotoxicity. Patients receiving gentamicin may experience neurotoxicity, manifesting as ototoxicity, including vestibular and auditory ototoxicity, primarily occurring in patients with pre-existing renal impairment and those with normal renal function receiving doses and/or treatment durations exceeding the recommended range. Ototoxicity caused by aminoglycosides is usually irreversible. Other manifestations of neurotoxicity may include numbness, tingling, muscle twitching, and seizures. Renal function and eighth cranial nerve function should be closely monitored, especially in patients with known or suspected renal impairment at the start of treatment, and in those initially with normal renal function who develop symptoms of renal dysfunction during treatment. Urine should be examined for decreased specific gravity, increased protein excretion, and the presence of cells or casts. Blood urea nitrogen (BUN), serum creatinine, or creatinine clearance should be measured regularly. If feasible, serial audiometry is recommended for patients of sufficient age to undergo hearing testing, particularly high-risk patients. If ototoxicity (dizziness, vertigo, tinnitus, booming in the ears, or hearing loss) or nephrotoxicity symptoms occur, dosage adjustment or discontinuation of the drug is necessary. As with other aminoglycosides, in rare cases, changes in renal and eighth cranial nerve function may not appear until shortly after treatment ends. Serum concentrations of aminoglycosides should be monitored as closely as possible to ensure adequate drug concentrations and avoid potential toxic levels. When monitoring peak gentamicin concentrations, the dosage should be adjusted to avoid concentrations exceeding 12 μg/mL for extended periods. When monitoring trough gentamicin concentrations, the dosage should be adjusted to avoid concentrations exceeding 2 μg/mL. Excessively high peak and/or trough serum concentrations of aminoglycosides may increase the risk of renal and eighth cranial nerve toxicity. In case of overdose or toxicity, hemodialysis can help remove gentamicin from the blood, especially in cases of impaired or deteriorating renal function. Peritoneal dialysis removes gentamicin much slower than hemodialysis. Exchange transfusion may also be considered for newborns. Concurrent or sequential systemic or local administration of other potentially neurotoxic and/or nephrotoxic drugs, such as cisplatin, cefazolin, kanamycin, amikacin, neomycin, polymyxin B, colistin, paromomycin, streptomycin, tobramycin, vancomycin, and purpuric acid, should be avoided. Other factors that may increase the risk of toxicity include advanced age and dehydration. Concurrent use of gentamicin and potent diuretics, such as ethacrynic acid or furosemide, should be avoided, as some diuretics themselves can cause ototoxicity. Furthermore, intravenous diuretics may enhance the toxicity of aminoglycosides by altering serum and tissue antibiotic concentrations. Aminoglycosides may harm the fetus when used in pregnant women. Hypersensitivity to gentamicin is a contraindication. Gentamicin may be contraindicated in patients with a history of hypersensitivity to other aminoglycosides or a history of severe toxic reactions, as cross-sensitivity to these drugs is known.
Use of aminoglycosides in pregnant women may harm the fetus. Aminoglycoside antibiotics can cross the placenta, and there have been several reported cases of children whose mothers received streptomycin during pregnancy developing complete, irreversible, bilateral congenital deafness. Other aminoglycoside antibiotics have not been reported to cause serious side effects in mothers, fetuses, or newborns. It is currently unclear whether the use of gentamicin sulfate in pregnant women will cause fetal harm or affect fertility. If gentamicin is used during pregnancy, or if a patient becomes pregnant while taking gentamicin, she should be informed of the potential risks to the fetus. Other reported adverse reactions possibly associated with gentamicin include: respiratory depression, somnolence, confusion, depression, visual disturbances, decreased appetite, weight loss, hypotension, and hypertension; rash, pruritus, urticaria, burning pain, laryngeal edema, anaphylactic reactions, fever, and headache; nausea, vomiting, increased salivation, and stomatitis; purpura, pseudotumor cerebri, acute organic brain syndrome, pulmonary fibrosis, alopecia, arthralgia, transient hepatomegaly, and splenomegaly. For more complete data on drug warnings (38 in total) for gentamicin, please visit the HSDB records page.

C60H123N15O21

477.603g/mol

477.316

C, 52.81; H, 9.08; N, 14.66; O, 23.45

1403-66-3

Gentamicin sulfate;1405-41-0

3467

White amorphous powder

1.3±0.1 g/cm3

669.4±55.0 °C at 760 mmHg

358.6±31.5 °C

0.0±4.6 mmHg at 25°C

1.583

-1.89

8

12

7

33

636

0

O([C@]1([H])[C@@]([H])([C@@]([H])([C@](C([H])([H])[H])(C([H])([H])O1)O[H])N([H])C([H])([H])[H])O[H])[C@@]1([H])[C@]([H])(C([H])([H])[C@@]([H])([C@@]([H])([C@@]1([H])O[H])O[C@@]1([H])[C@]([H])(C([H])([H])C([H])([H])[C@@]([H])([C@]([H])(C([H])([H])[H])N([H])C([H])([H])[H])O1)N([H])[H])N([H])[H])N([H])[H]

CEAZRRDELHUEMR-UHFFFAOYSA-N

InChI=1S/C21H43N5O7/c1-9(25-3)13-6-5-10(22)19(31-13)32-16-11(23)7-12(24)17(14(16)27)33-20-15(28)18(26-4)21(2,29)8-30-20/h9-20,25-29H,5-8,22-24H2,1-4H3

2-[4,6-diamino-3-[3-amino-6-[1-(methylamino)ethyl]oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol

Septigen; Uromycine; Centicin; Refobacin; Oksitselanim; Lyramycin

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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

H2O: ~175 mg/mL

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.)