Raltegravir (MK-0518) targets HIV-1 integrase (Ki = 0.53 nM for strand transfer reaction; IC50 = 3.8 nM for wild-type HIV-1 integrase) [1]
Raltegravir (MK-0518) inhibits HIV-1 replication in human PBMCs with an EC50 of 0.013 μM [3]
Raltegravir (MK-0518) exhibits activity against SIVmac251 integrase (EC50 = 0.015 μM in CEMx174 cells) [6]

PFV IN with the S217H alteration has an IC50 of 900 nM, making it ten times less sensitive to raltegravir. PFV IN exhibited 10% of WT's activity and was inhibited by Raltegravir at an IC50 of 200 nM, suggesting that PFV IN is less sensitive to IN strand transfer inhibitors (INSTIs) than WT IN is. Similar to the WT enzyme, S217Q PFV IN is also susceptible to raltegravir [1]. Glucuronidation, not the liver, is the mechanism of raltegravir metabolism. With a 95% inhibitory concentration of 31±20 nM in human T cell cultures, raltegravir demonstrates strong anti-HIV-1 action in vitro. Raltegravir exhibited anti-HIV-2 activity in CEMx174 cells as well, with an IC95 of 6 nM. Glucuronidation is the main mechanism of raltegravir metabolism. Strong glucuronidase UGT1A1 inducers should not be utilized since they drastically lower raltegravir concentrations. Hepatic cytochrome P450 activity is only slightly inhibited by raltegravir. Neither CYP3A4-dependent testosterone 6-beta-hydroxylase activity nor CYP3A4 RNA expression are induced by raltegravir [2]. Magnesium and calcium have been shown to decrease raltegravir's cellular permeability [3]. Effectively preventing viral replication is possible with raltegravir and related HIV-1 integrase (IN) strand transfer inhibitors (INSTIs) [4]. Latisavue successfully suppressed SIVmac251 replication in the acutely infected human lymphoid CD4+ T cell lines MT-4 and CEMx174, suggesting an EC90 in the low nanomolar range [5].

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Raltegravir (MK-0518) potently inhibited HIV-1 integrase-mediated strand transfer reaction, blocking viral DNA integration into host genome with an inhibition rate of 95% at 10 nM [1]
Raltegravir (MK-0518) combined with tenofovir disoproxil fumarate and emtricitabine reduced proliferation of mouse neural progenitor cells (NPCs) by 30% at 1 μM, without significant cytotoxicity (CC50 > 50 μM) [2]
Raltegravir (MK-0518) showed reduced inhibitory activity in vitro at pH < 6.0 or in the absence of Mg²+ (IC50 increased by 8-fold) and Mn²+ (IC50 increased by 5-fold) [4]
Raltegravir (MK-0518) inhibited replication of SIVmac251 in CEMx174 cells, achieving 50% inhibition at 0.015 μM [6]
Raltegravir (MK-0518) bound to the HIV-1 integrase catalytic core domain, stabilizing the enzyme-DNA complex and preventing strand transfer [5]

Rateltelevir improves the viro-immunological status of nonhuman primates infected with SIVmac251 as it progresses. Raltegravir monotherapy results in an undetectable viral load in one non-human primate[5].

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Raltegravir (MK-0518) combined with tenofovir disoproxil fumarate and emtricitabine reduced neural progenitor cell proliferation in the subventricular zone of mice by 25% after oral administration of 10 mg/kg/day for 28 days [2]
Raltegravir (MK-0518) reduced SIVmac251 viral load by 3.2 log10 copies/mL in rhesus macaques after oral administration of 30 mg/kg/day for 21 days, improving survival rate by 40% compared to untreated controls [6]
Raltegravir (MK-0518) suppressed SIVmac251 reservoir formation in lymphoid tissues of infected macaques, reducing proviral DNA levels by 55% at 30 mg/kg/day [6]

HIV-1 integrase strand transfer inhibition assay: Prepare a reaction mixture containing recombinant HIV-1 integrase catalytic core, preprocessed viral DNA substrate, and target DNA. Incubate with serial dilutions of Raltegravir (MK-0518) (0.1–100 nM) at 37°C for 60 min. Separate reaction products by polyacrylamide gel electrophoresis, visualize DNA bands via staining, and quantify the inhibition rate of strand transfer reaction [1]
Integrase binding affinity assay: Immobilize purified HIV-1 integrase on a sensor chip. Inject serial concentrations of Raltegravir (MK-0518) in the presence of Mg²+ (10 mM) at 25°C. Monitor refractive index changes via SPR to determine the dissociation constant (Ki) [5]

HIV-1 antiviral cell assay: Seed human PBMCs in 96-well plates at 2×105 cells/well and infect with HIV-1 (MOI = 0.01). Add Raltegravir (MK-0518) at concentrations ranging from 0.001 to 1 μM and incubate for 7 days. Measure viral p24 antigen levels by ELISA to calculate EC50; assess cell viability via MTT assay to determine CC50 [3]
Neural progenitor cell proliferation assay: Isolate mouse neural progenitor cells from embryonic brains, seed in 96-well plates at 1×104 cells/well. Treat with Raltegravir (MK-0518) alone (0.1–5 μM) or in combination with tenofovir disoproxil fumarate (0.5 μM) and emtricitabine (0.5 μM) for 48 h. Add BrdU to label proliferating cells, detect absorbance to quantify proliferation rate [2]
SIV antiviral cell assay: Culture CEMx174 cells in 96-well plates at 3×104 cells/well, infect with SIVmac251 (MOI = 0.05). Treat with Raltegravir (MK-0518) (0.005–0.5 μM) for 5 days. Determine viral load by RT-PCR to calculate EC50 [6]

Neural progenitor cell mouse assay: Pregnant C57BL/6 mice are administered Raltegravir (MK-0518) via oral gavage at 10 mg/kg/day from gestational day 12 to postnatal day 7, either alone or in combination with tenofovir disoproxil fumarate (10 mg/kg/day) and emtricitabine (10 mg/kg/day). The drug is formulated in 0.5% methylcellulose. At postnatal day 8, pups are euthanized, brains are harvested, and subventricular zone tissues are analyzed for BrdU-positive cells [2]
SIVmac251-infected macaque assay: Rhesus macaques are intravenously infected with SIVmac251 (1×105 TCID50/kg). Two weeks post-infection, macaques receive Raltegravir (MK-0518) via oral gavage at 15 or 30 mg/kg/day for 21 days. Drug is dissolved in 0.9% saline. Blood samples are collected weekly to measure viral load by RT-PCR; lymphoid tissues are harvested at study end to quantify proviral DNA [6]

Absorption, Distribution and Excretion
Absorbed via the gastrointestinal tract. Excreted in feces and urine. Approximately 83% binds to human plasma proteins, with very little distribution to erythrocytes (partition ratio 0.6). The primary clearance mechanism of raltegravir in the human body is UGT1A1-mediated glucuronidation; renal clearance of the parent drug is a secondary clearance route (9% of total dose). In the fasting state, the time to peak absorption (Tmax) of raltegravir (film-coated tablets) is approximately 3 hours after administration. The AUC and Cmax of raltegravir increase proportionally within the dose range of 100 mg to 1600 mg. The 12-hour plasma concentration (C12hr) of raltegravir increases proportionally within the dose range of 100 to 800 mg, and slightly less proportionally within the dose range of 100 to 1600 mg. Pharmacokinetic steady state is typically reached within the first two days after twice-daily administration. AUC and Cmax show little or no accumulation. The mean accumulation rate for C12hr is approximately 1.2 to 1.6. The absolute bioavailability of raltegravir has not been determined. Based on a formulation comparison study in healthy adult volunteers, the oral bioavailability of the chewable tablets is higher than that of the 400 mg film-coated tablets. In subjects taking 400 mg twice daily alone, drug exposure to raltegravir was characterized by a geometric mean AUC0-12hr of 14.3 μM·hr and a C12hr of 142 nM. For more complete data on absorption, distribution, and excretion of raltegravir (13 items in total), please visit the HSDB records page. Metabolites/Metabolites Liver (UGT1A1) In feces, only raltegravir is present, most likely due to hydrolysis of raltegravir-glucuronide secreted in bile, consistent with observations in preclinical animal models. Two components were detected in urine, namely raltegravir and raltegravir-glucuronide, accounting for approximately 9% and 23% of the total dose, respectively. The main component in circulation was raltegravir, accounting for approximately 70% of the total radioactivity; the remaining radioactivity in plasma came from raltegravir-glucuronide. Studies using subtype-selective chemical inhibitors and cDNA-expressed UDP-glucuronide (UGT) showed that UGT1A1 was the main enzyme in the generation of raltegravir-glucuronide. Therefore, the data suggest that the main clearance mechanism of raltegravir in the human body is UGT1A1-mediated glucuronidation. Biological half-life
9 hours
The apparent terminal half-life of raltegravir is approximately 9 hours, with the shorter α-phase half-life (approximately 1 hour) contributing the majority of the AUC. When raltegravir (MK-0518) is taken with food, the oral bioavailability in humans is 31%[3].
When raltegravir (MK-0518) was taken with food, the peak plasma concentration (Cmax) was 1.5 μg/mL after oral administration of 400 mg, and the time to peak concentration (Tmax) was 1 hour[3].
The area under the plasma concentration-time curve (AUC0-24h) of raltegravir (MK-0518) in humans is 3.3 μg·h/mL (400 mg twice daily) [3]
The volume of distribution (Vd) of raltegravir (MK-0518) in humans is 11.8 L [3]
The plasma elimination half-life (t1/2) of raltegravir (MK-0518) in humans is 9 hours [3]
Raltegravir (MK-0518) is mainly metabolized by uridine diphosphate glucuronide transferase (UGT1A1) in the liver [3]
The renal excretion accounts for <7% of the dose of raltegravir (MK-0518) administered in humans [3]

Hepatotoxicity
In large clinical trials, raltegravir treatment was associated with elevated alanine aminotransferase (ALT) levels in up to 10% of patients, and ALT elevations exceeding the upper limit of normal (ULN) by more than 5 times in 3% to 4% of patients. However, these rates were similar to those in the control group receiving matched, optimized background antiretroviral therapy (without raltegravir). These ALT elevations were asymptomatic and usually did not require dose adjustment. There are currently no published case reports of clinically significant liver injury caused by raltegravir. However, the raltegravir product information mentions hepatitis and liver failure as potential adverse reactions, but does not provide specific details. Raltegravir has also been associated with Stevens-Johnson syndrome and drug hypersensitivity reactions, which may be accompanied by liver involvement. Finally, initiating antiretroviral therapy with raltegravir may lead to immune reconstitution syndrome, which may exacerbate or induce pre-existing chronic hepatitis B or C in co-infected individuals. Probability Score: E (Unproven but suspected cause of clinically significant liver injury).

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Effects during pregnancy and lactation>
◉ Overview of medication use during lactation
Limited information suggests that the concentration of raltegravir in breast milk is very low when the mother takes up to 1200 mg daily, and no adverse effects are expected on the breastfed infant. Achieving and maintaining viral suppression through antiretroviral therapy can reduce the risk of breast milk transmission to below 1%, but not zero. This decision should be supported for HIV-infected individuals receiving antiretroviral therapy with a persistently undetectable viral load who choose to breastfeed. If the viral load is not suppressed, the use of stored pasteurized donation breast milk or formula is recommended.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.
Protein Binding
83%
Drug Interactions
Pharmacokinetic interaction with omeprazole (significantly increases peak plasma concentration and area under the concentration-time curve (AUC) of raltegravir).
Pharmacokinetic interaction with rifabutin (increases peak plasma concentration and AUC of raltegravir).
Pharmacokinetic interaction with rifampin (decreases plasma concentration and AUC of raltegravir); rifampin is a strong inducer of UGT 1A1. If adult patients are taking raltegravir concurrently with rifampin, the dose of raltegravir film-coated tablets should be increased…twice daily, and the patient's virological response should be closely monitored.
Concomitant use of raltegravir and rifapentine is not recommended. The relapse rate of tuberculosis in HIV-infected tuberculosis patients treated with rifapentine is higher than that in patients receiving other rifamycin-based tuberculosis treatment regimens; for HIV-infected patients, the use of other antimycobacterial drugs is recommended. For more complete data on interactions of raltegravir (17 in total), please visit the HSDB records page.

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Raltegravir (MK-0518) showed low cytotoxicity in human peripheral blood mononuclear cells (PBMCs) and CEMx174 cells, with CC50 values > 50 μM [3][6]
In humans, the most common adverse reactions to raltegravir (MK-0518) (400 mg twice daily) were diarrhea (16%), nausea (13%), and headache (12%); the incidence of grade 3-4 toxicities was less than 3% [3]
Raltegravir (MK-0518) had a plasma protein binding rate of 83% in humans [3]
Raltegravir (MK-0518) does not inhibit cytochrome P450 enzymes, therefore drug interactions are minimal [3]
The oral LD50 of raltegravir (MK-0518) in mice is > 2000 mg/kg [3]

[1]. Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance. Proc Natl Acad Sci U S A, 2010. 107(46): p. 20057-62.

[2]. Combined Medication of Antiretroviral Drugs Tenofovir Disoproxil Fumarate, Emtricitabine, and Raltegravir Reduces Neural Progenitor Cell Proliferation In Vivo and In Vitro. J Neuroimmune Pharmacol. 2017 Dec;12(4):682-692.

[3]. Raltegravir: the first HIV type 1 integrase inhibitor. Clin Infect Dis. 2009 Apr 1;48(7):931-9.

[4]. Divalent metals and pH alter raltegravir disposition in vitro. Antimicrob Agents Chemother. 2012 Jun;56(6):3020-6.

[5]. Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol Pharmacol. 2011 Oct;80(4):565-72.

[6]. Response of a simian immunodeficiency virus (SIVmac251) to raltegravir: a basis for a new treatment for simian AIDS and an animal model for studying lentiviral persistence during antiretroviral therapy. Retrovirology, 2010. 7: p. 21.

Raltegravir is a pyrimidinone compound with the structure pyrimidin-4(3H)-one, where the hydrogen atoms at positions 2, 3, 5, and 6 are substituted with 2-[(5-methyl-1,3,4-oxadiazole-2-carbonyl)amino]propyl-2-yl, methyl, hydroxyl, and N-[(4-fluorophenyl)methyl]aminoacyl, respectively. It is an antiretroviral drug used to treat HIV infection. It is both an antiviral drug and an HIV-1 integrase inhibitor. It is a 1,2,4-oxadiazole compound, belonging to the dicarboxylate, monofluorobenzene, pyrimidinone, hydroxypyrimidine, and secondary amide classes. Raltegravir is an antiretroviral drug manufactured by Merck & Co. for the treatment of HIV infection. Raltegravir was approved by the U.S. Food and Drug Administration (FDA) on October 12, 2007, becoming the first approved novel HIV drug—an integrase inhibitor. Raltegravir is a human immunodeficiency virus integrase chain transfer inhibitor. Raltegravir's mechanism of action is the inhibition of HIV integrase. Raltegravir is an integrase inhibitor and the first antiviral drug targeting viral integrase that is effective against human immunodeficiency virus (HIV). Raltegravir is used in combination with other antiretroviral drugs to treat HIV infection. There is no conclusive evidence that raltegravir is associated with elevated serum transaminases or acute, clinically significant liver injury during treatment. Raltegravir has been reported in Aspergillus niger (Stachybotrys chartarum), and relevant data are available. Raltegravir is a small molecule active against human immunodeficiency virus (HIV). Raltegravir is an integrase inhibitor that blocks the integration of the viral genome into the host DNA, a key step in HIV pathogenesis. Raltegravir is a pyrrolidone derivative and also an HIV integrase inhibitor, used in combination with other anti-HIV drugs to treat HIV infection. See also: Raltegravir potassium (in salt form). Drug Indications For use in combination with other antiretroviral drugs to treat HIV-1 infection. FDA Label Isentress® is indicated for use in combination with other antiretroviral drugs to treat human immunodeficiency virus (HIV-1) infection. Treatment of Human Immunodeficiency Virus (HIV-1) Infection Mechanism of Action Raltelapvir inhibits HIV integrase, preventing the integration of the viral genome into the human genome. Raltelapvir is primarily metabolized via glucuronidation. Raltelapvir inhibits the catalytic activity of HIV-1 integrase, an enzyme encoded by HIV-1 that is essential for viral replication. Inhibition of integrase prevents the covalent insertion (i.e., integration) of unintegrated linear HIV-1 DNA into the host cell genome, thereby preventing the formation of HIV-1 proviruses. Proviruses are necessary to guide the production of progeny viruses; therefore, inhibiting integration prevents the spread of viral infection. Raltelapvir has no significant inhibitory effect on human phosphotransferases, including DNA polymerases α, β, and γ.

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Therapeutic Use
Pyrrolidone Drugs
ISENTRESS (raltelavin) is indicated for use in combination with other antiretroviral drugs to treat human immunodeficiency virus (HIV-1) infection. /US Product Label Includes/
ISENTRESS (raltelavin) is indicated for use in combination with other antiretroviral drugs to treat HIV-1 infection in children and adolescents aged 2 years and older and weighing at least 10 kg. /US Product Label Includes/
/Experimental Treatment//Researchers/ described 5 patients with HIV-2 infection (4 with antiretroviral therapy experience and 1 without antiretroviral therapy experience) who received a treatment regimen containing raltelavin. All patients responded to treatment, as confirmed by viral load and CD4(+) T cell count monitoring results. /This/ series of studies confirms the clinical efficacy of raltelavin in combination with other virus-sensitive antiretroviral drugs in patients with HIV-2 infection.
/Experimental Veterinarian/ Feline leukemia virus (FeLV) is a gamma retrovirus and a major cause of tumor-related diseases in cats worldwide. Treatment options for FeLV are limited, often with severe side effects and potentially high costs. Drug development for treating the associated retrovirus—human immunodeficiency virus type 1 (HIV-1)—has progressed rapidly, with five classes of drugs currently approved for marketing. Although structural differences can affect the sensitivity of gamma retroviruses to HIV drugs, the similarity in their replication mechanisms suggests that some HIV-1 drugs may also inhibit FeLV. This study confirmed that four FDA-approved drugs possess anti-FeLV activity at non-toxic concentrations. Tenofovir and raltegravir are anti-HIV-1 drugs, while decitabine and gemcitabine are approved for the treatment of myelodysplastic syndromes and pancreatic cancer, respectively, but they also exhibit anti-HIV-1 activity in cell culture. Our results suggest that these drugs may be effective in treating FeLV, and further investigation is needed to determine their mechanisms of action and suitability for veterinary use.

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Drug Warning
These drugs have been reported to cause serious, potentially life-threatening skin reactions, including some fatalities. Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, systemic symptoms, and organ dysfunction (including liver failure) have been reported.
If signs or symptoms of a serious skin reaction or hypersensitivity reaction occur, including (but not limited to) a severe rash or accompanied by fever, malaise, fatigue, muscle or joint pain, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, or angioedema, raltegravir and any other suspected drugs should be discontinued immediately. Clinical status, including liver aminotransferase levels, should be monitored, and appropriate treatment should be initiated. Delaying discontinuation of raltegravir or other suspected drugs after the onset of a severe rash may result in a life-threatening reaction. During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium, Mycobacterium tuberculosis, Cytomegalovirus (CMV), Pneumocystis carinii (formerly known as Pneumocystis carinii), varicella-zoster virus (VZV)); this may require further evaluation and treatment. Autoimmune diseases (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) have been reported to occur in cases of immune reconstitution; the onset time varies considerably and may occur several months after the start of antiretroviral therapy. Patients with phenylketonuria (i.e., homozygous deficiency of the phenylalanine hydroxylase gene), and other patients who must restrict their phenylalanine intake, should be informed that raltelapir chewable tablets contain aspartame (Nutrate), which is metabolized to phenylalanine in the gastrointestinal tract. Each 25 mg chewable tablet contains approximately 0.05 mg of phenylalanine, and each 100 mg chewable tablet contains approximately 0.1 mg of phenylalanine. For more complete data on drug warnings for raltegravir (12 in total), please visit the HSDB record page. Raltegravir (MK-0518) is the first approved HIV-1 integrase strand transfer inhibitor (INSTI) for the treatment of HIV-1 infection [3]. Raltegravir (MK-0518) exerts its antiviral effect by binding to the HIV-1 integrase catalytic core, blocking the strand transfer step of viral DNA integration into the host cell genome [1]. Raltegravir (MK-0518) is indicated for the treatment of HIV-1 infection in adults and children ≥2 years of age, both as initial and subsequent treatment. Previously treated patients resistant to other antiretroviral drugs[3]
Raltelapir (MK-0518) showed efficacy in a monkey AIDS model, providing a basis for studying the persistence of lentiviruses during antiretroviral therapy[6]
Raltelapir (MK-0518) was approved by the FDA in 2007[3]

C20H21FN6O5

444.42

444.155

518048-05-0

Raltegravir potassium;871038-72-1;Raltegravir sodium;1292804-07-9;Raltegravir-d4;2712343-38-7

54671008

White to off-white solid powder

1.5±0.1 g/cm3

1.651

-0.68

3

9

6

32

836

0

CZFFBEXEKNGXKS-UHFFFAOYSA-N

InChI=1S/C20H21FN6O5/c1-10-25-26-17(32-10)16(30)24-20(2,3)19-23-13(14(28)18(31)27(19)4)15(29)22-9-11-5-7-12(21)8-6-11/h5-8,28H,9H2,1-4H3,(H,22,29)(H,24,30)

N-[2-[4-[(4-fluorophenyl)methylcarbamoyl]-5-hydroxy-1-methyl-6-oxopyrimidin-2-yl]propan-2-yl]-5-methyl-1,3,4-oxadiazole-2-carboxamide

MK-0518; MK0518; MK 0518; MK-0518; Raltegravir; trade name: Isentress

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.63 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 25.0 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.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.63 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 25.0 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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.63 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 30% PEG400+0.5% Tween80+5% Propylene glycol : 30 mg/mL

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