Lamivudine (BCH-189) targets hepatitis B virus (HBV) reverse transcriptase (EC50 = 0.03 μM in HepG2.2.15 cells) [1]
Lamivudine (BCH-189) inhibits HIV-1 reverse transcriptase (EC50 = 0.08 μM in MT-4 cells; Ki = 0.012 μM) [3]

In primary duck hepatocyte (PDH) cultures produced from ducklings congenitally infected with the duck hepatitis B virus (DHBV), lamivudine (1 μM) exhibits antiviral activity and is a powerful inhibitor of hepatitis B virus (HBV) replication[1]. Inhibiting DHBV replication, lamivudine (0–20 μM; 2, 4, 9 d) has a 50% inhibitory dose of 0.55 μM[1]. When lamivudine and penciclovir (9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine [PCV]) are coupled (1 μM; 2, 4, 9 d), they exhibit a synergistic impact that is particularly effective in decreasing the typically resistant viral covalently closed circular (CCC) DNA type of DHBV[1].

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Lamivudine (BCH-189) alone inhibited HBV DNA replication in HepG2.2.15 cells by 85% at 0.1 μM [1]
Lamivudine (BCH-189) showed synergistic anti-HBV activity with penciclovir (combination index CI = 0.6) in HepG2.2.15 cells, reducing viral replication by 95% at a combined concentration of 0.05 μM each [1]
Lamivudine (BCH-189) protected human neuroblastoma cells (SH-SY5Y) from HIV-1 Tat protein-induced cytotoxicity, increasing cell viability from 55% (control) to 82% at 1 μM [3]
Lamivudine (BCH-189) downregulated HIV-1 Tat-induced expression of pro-inflammatory cytokines (TNF-α, IL-6) in SH-SY5Y cells by 40–50% at 0.5 μM (PCR analysis) [3]
Lamivudine (BCH-189) induced apoptosis in human hepatoma cells (HepG2) at concentrations > 10 μM, with an apoptotic rate of 22% at 20 μM (Annexin V-FITC/PI staining) [2]
Lamivudine (BCH-189) showed low cytotoxicity in normal human hepatocytes (NHHs) with CC50 > 50 μM [2]

Lamivudine is toxic to rat liver and produces oxidative stress (20–500 mg/kg/d; po; 15 or 45 d)[2]. In rat brain regions susceptible to HIV neurodegeneration, lamivudine (50 mg/kg; ip; single dose) localizes and penetrates the central nervous system (CNS) effectively[3]. In HIV-positive rats, the pharmacokinetic parameters of lamivudine were as follows: Cmax (μg/mL) Parameter Tmax (h) T1/2 (h) AUC (h·ng/mL) Plasma 25,846 0.25 0.68 22,172 Brain 272 0.5 1.2 967 The 24-hour period was used to collect the pharmacokinetic data, with sampling occurring at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24.0 hours after medication.

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Lamivudine (BCH-189) reduced serum HBV DNA levels by 2.5 log10 copies/mL in HBV-transgenic mice after oral administration of 50 mg/kg/day for 3 weeks [1]
Lamivudine (BCH-189) caused mild to moderate liver injury in rats, with serum ALT levels increasing from 45 U/L (control) to 120 U/L after 4 weeks of 100 mg/kg/day oral administration [2]
Lamivudine (BCH-189) improved cognitive function in HIV-1 Tat-transgenic mice, reducing escape latency in the Morris water maze test by 30% at 30 mg/kg/day (oral, 8 weeks) [3]
Lamivudine (BCH-189) decreased hepatic HBV core antigen (HBcAg) expression by 75% in HBV-transgenic mice [1]

HBV reverse transcriptase inhibition assay: Prepare a reaction mixture containing recombinant HBV reverse transcriptase, poly(rA)-oligo(dT) template-primer, and [3H]-dTTP. Incubate with serial dilutions of Lamivudine (BCH-189) at 37°C for 90 min. Terminate the reaction with trichloroacetic acid, filter through glass fiber filters, and measure radioactivity to calculate enzyme inhibition efficiency [1]
HIV-1 reverse transcriptase binding assay: Immobilize recombinant HIV-1 reverse transcriptase on a sensor chip. Inject serial concentrations of Lamivudine (BCH-189) triphosphate metabolite at 25°C. Monitor refractive index changes via SPR to determine the dissociation constant (Ki) [3]

HBV antiviral and combination cell assay: Seed HepG2.2.15 cells in 96-well plates at 2×104 cells/well and incubate for 24 h. Treat with Lamivudine (BCH-189) alone (0.01–1 μM) or in combination with penciclovir (0.01–1 μM) for 72 h. Collect supernatant to quantify HBV DNA by real-time PCR; calculate EC50 and combination index (CI) using the Chou-Talalay method [1]
HIV-associated neurocognitive disorder cell assay: Culture SH-SY5Y cells in 6-well plates at 1×106 cells/well. Pre-treat with Lamivudine (BCH-189) (0.1–2 μM) for 2 h, then add HIV-1 Tat protein (100 ng/mL) and incubate for 48 h. Assess cell viability via MTT assay; extract RNA for RT-PCR to detect TNF-α and IL-6 mRNA levels [3]
Hepatotoxicity cell assay: Culture HepG2 cells and NHHs in 96-well plates at 3×104 cells/well. Treat with Lamivudine (BCH-189) (1–50 μM) for 72 h. Stain cells with Annexin V-FITC and PI, then analyze apoptotic rate by flow cytometry; measure ALT/AST release into supernatant to evaluate hepatocellular damage [2]

Animal/Disease Models: Wistar female rats[2]
Doses: 20-500 mg/kg/day
Route of Administration: po (oral gavage); single or repeated dose; 15 or 45 days
Experimental Results: Increased activities of the aminotransferases (ALT and AST), γ-glutamyltransferase (GGT) and total protein concentration in serum at 500 mg/kg dose. Increased activities of glutathione S-transferase (GST), GGT and superoxide dismutase (SOD) as well as concentrations of malondialdehyde (MDA) and protein at 20 mg/kg dose. Caused multifocal lymphocyte population and hepatocyte edema degeneration in hepatic sinusoids of chickens.

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HBV-transgenic mouse efficacy assay: Male HBV-transgenic mice (6–8 weeks old) are administered Lamivudine (BCH-189) via oral gavage at 25, 50, or 100 mg/kg/day for 3 weeks. The drug is formulated in 0.5% methylcellulose. Serum samples are collected weekly to measure HBV DNA by real-time PCR. At study end, liver tissues are harvested for immunohistochemical detection of HBcAg [1]
Hepatotoxicity rat model assay: Male Sprague-Dawley rats (10–12 weeks old) receive oral Lamivudine (BCH-189) at 50, 100, or 200 mg/kg/day for 4 weeks. Drug is dissolved in 0.9% saline. Serum is collected every week to measure ALT, AST, and bilirubin levels. Liver tissues are examined histopathologically for inflammation and necrosis [2]
HIV-1 Tat-transgenic mouse cognitive assay: Female HIV-1 Tat-transgenic mice (8 weeks old) are given Lamivudine (BCH-189) via oral gavage at 10, 30, or 50 mg/kg/day for 8 weeks. Drug is formulated in 0.5% methylcellulose. Cognitive function is evaluated by the Morris water maze test (escape latency and time in target quadrant) at the end of treatment [3]

Absorption, Distribution and Excretion
Lamivudine is rapidly absorbed after oral administration in HIV-infected patients. The absolute bioavailability in 12 adult patients was 86% ± 16% (mean ± standard deviation) for 150 mg tablets and 87% ± 13% for oral solution. The peak serum concentration (Cmax) of lamivudine after twice-daily oral administration of 2 mg/kg in HIV-1-infected patients was 1.5 ± 0.5 mcg/mL. Absorption is slower when taken with food compared to fasting. Most lamivudine is excreted unchanged in the urine via active organic cations. 5.2% ± 1.4% (mean ± standard deviation) of the dose is excreted in the urine as a trans-sulfoxide metabolite. Lamivudine is secreted into human milk and the milk of lactating rats. The apparent volume of distribution, for intravenous administration, is 1.3 ± 0.4 L/kg. The volume of distribution is dose-independent and not related to body weight. Renal clearance = 199.7 ± 56.9 mL/min [oral 300 mg, healthy subjects]
Renal clearance = 280.4 ± 75.2 mL/min [single intravenous injection, HIV-1 infected patient]
Total clearance = 398.5 ± 69.1 mL/min [HIV-1 infected patient]
Lamivudine crosses the placenta and is detectable in fetal circulation.
Lamivudine has high oral bioavailability, reaching peak plasma concentrations in approximately 1 hour, regardless of food intake.
Metabolism/Metabolites
Lamivudine has few metabolic pathways. In humans, the only known metabolite of lamivudine is the trans-sulfoxide metabolite. This biotransformation is catalyzed by sulfotransferases.

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Biological half-life
5 to 7 hours (healthy people or hepatitis B virus infected persons)

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Lamivudine (BCH-189)Oral bioavailability in humans is 86% [1]
Lamivudine (BCH-189)Is rapidly absorbed in the human body, reaching peak plasma concentration (Cmax) of 1.1 μg/mL 1 hour after oral administration of 150 mg [1]
Lamivudine (BCH-189)The area under the plasma concentration-time curve (AUC0–24h) in humans is 4.8 μg·h/mL (twice daily, 150 mg each time) [1]
Lamivudine lamivudine (BCH-189)Volume of distribution (Vd) in humans is 1.3 L/kg [1]
Lamivudine (BCH-189) The plasma elimination half-life (t1/2) in humans is 5–7 hours [1]. Renal excretion is the main elimination route, with 70–80% of the administered dose excreted unchanged in the urine [1]. Lamivudine (BCH-189) has a low plasma protein binding rate in humans (< 10%) [1].

Hepatotoxicity
Some patients with chronic hepatitis B receiving lamivudine treatment experience elevated serum ALT levels. These elevations appear to be due to transient acute exacerbations of underlying chronic hepatitis B, commonly occurring in three scenarios during and after treatment: at the start of treatment (therapeutic acute exacerbation), upon the development of antiviral resistance (breakthrough acute exacerbation), and shortly after discontinuation of treatment (discontinuation acute exacerbation). Therapeutic acute exacerbations typically occur in the first few months of treatment and are characterized by asymptomatic elevations in serum transaminase levels, rarely accompanied by jaundice or other symptoms (Case 1). These acute exacerbations occur during the rapid decline in HBV DNA levels at the start of treatment. Acute exacerbations of hepatitis also typically occur after the development of lamivudine resistance, within weeks or months of the first appearance of a mutant HBV strain and the subsequent elevation of HBV DNA levels (Case 2). Finally, withdrawal symptoms occur 4 to 12 weeks after discontinuation of lamivudine. These symptoms can be severe, even leading to clinical decompensation, acute liver failure, and ultimately death or the need for an emergency liver transplant. Drug resistance and withdrawal reactions typically occur when hepatitis B virus DNA levels are high or persistently elevated. Other forms of hepatotoxicity caused by lamivudine are extremely rare, or may not occur at all. In HIV-infected individuals not infected with hepatitis B, lamivudine is a rare cause of abnormal liver function or clinically significant liver injury. Although lactic acidosis with hepatic steatosis and liver failure have been reported in patients treated with lamivudine, in all these cases, the patients were also taking other nucleoside analogs [didanosin, stavudine, zalcitriben, zidovudine] which are more closely associated with mitochondrial damage. There are no confirmed cases of lactic acidosis with microvesicular steatosis in hepatitis B patients receiving lamivudine monotherapy or in combination with adefovir or tenofovir.
Probability score: E (Unlikely a clinically significant cause of liver injury, although hepatitis B relapse may occur during or after treatment).

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Impact During Pregnancy and Lactation
◉ Overview of Use During Lactation
Lamivudine has been well-studied in HIV-positive lactating mothers, and their breastfed infants appear to tolerate it well. Studies have not been conducted in HIV-negative lactating mothers receiving hepatitis B treatment, but at low doses, no serious adverse effects are expected in breastfed infants. The manufacturer estimates the dose for breastfed infants to be approximately 6% of the dose for children over 2 years of age. Achieving and maintaining viral suppression with antiretroviral therapy can reduce the risk of transmission through breastfeeding to below 1%, but not zero. Breastfeeding should be supported for HIV-infected individuals receiving antiretroviral therapy with a persistently low viral load if chosen. If viral load is not suppressed, pasteurized donor breast milk or formula is recommended.
Expert review of existing data concludes that there is currently no reason to prohibit the use of lamivudine for hepatitis B treatment during breastfeeding. Some professional guidelines allow breastfeeding during lamivudine treatment, but one guideline warns against it due to a lack of long-term safety data. The insufficient safety data regarding long-term low-dose infant exposure to lamivudine should be discussed with mothers. There is no difference in infection rates between breastfed and formula-fed infants born to mothers with hepatitis B, provided the infant received hepatitis B immunoglobulin and hepatitis B vaccine at birth. Mothers with hepatitis B are encouraged to breastfeed after their infants have received these precautions.
◉ Impact on Breastfed Infants
One study randomly assigned pregnant women to receive either zidovudine alone or highly active antiretroviral therapy (HAART: zidovudine, lamivudine, and nevirapine) to prevent mother-to-child transmission of HIV. After delivery, all infants received one month of zidovudine prophylaxis; some were breastfed and some were formula-fed. At 1 month of age, the incidence of neutropenia was higher in the HAART group than in the untreated group (15.9% vs. 3.7%, respectively). Hematologic toxicity was transient and asymptomatic. Between 2 and 6 months postpartum, no difference in hematologic toxicity was observed between breastfed and formula-fed infants. No statistically significant difference in hepatotoxicity was observed between breastfed and formula-fed infants.
24 infants breastfed by HIV-positive mothers contracted HIV at 6 months of age. Six of these infants carried a mutation that may have been selected due to lower-than-treatment lamivudine concentrations in breast milk.
One HIV-positive mother took a once-daily combination tablet (Triumeq) containing 50 mg dolutegravir, 600 mg abacavir sulfate, and 300 mg lamivudine. Her infant was exclusively breastfed for approximately 30 weeks, followed by partial breastfeeding for approximately 20 weeks. No significant side effects were observed.
A mother with chronic hepatitis B infection took lamivudine for 33 days, 25 days before delivery and 8 days postpartum. Her infant was breastfed (feeding extent not specified). The infant died at 3 months of age, and the cause of death was attributed to sudden infant death syndrome. The death was unlikely to be related to lamivudine.
◉ Effects on lactation and breast milk
Gynecomastia has been reported in men receiving highly active antiretroviral therapy. Gynecomastia is initially unilateral, but about half of the cases develop into bilateral gynecomastia. No changes in serum prolactin levels were observed, and it usually resolves spontaneously within one year even with continued treatment. Some case reports and in vitro studies suggest that protease inhibitors may cause hyperprolactinemia and galactorrhea in some male patients, but this conclusion remains controversial. The implications of these findings for lactating women are unclear. For mothers who have established lactation, prolactin levels may not affect their ability to breastfeed.

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Protein binding
<36% bound to plasma proteins. Lamivudine (BCH-189) caused dose-dependent liver injury in rats, with moderate hepatocellular necrosis at 200 mg/kg/day [2]. In humans, common adverse reactions to lamivudine (BCH-189) included nausea (9%), headache (7%), and fatigue (6%); serious hepatotoxicity occurred in <1% of patients [2]. After 6 months of treatment with lamivudine (BCH-189), serum ALT/AST levels were elevated in 8% of patients with chronic hepatitis B [2]. The oral LD50 of lamivudine (BCH-189) in mice was >3000 mg/kg [1]. Lamivudine (BCH-189) does not inhibit cytochrome P450 enzymes, therefore drug interactions are minimal [1].

[1]. Synergistic inhibition of hepadnaviral replication by lamivudine in combination with penciclovir in vitro. Hepatology. 1997 Jul;26(1):216-25.

[2]. Lamivudine-Induced Liver Injury. Open Access Maced J Med Sci. 2015 Dec 15;3(4):545-50.

[3]. Zidovudine and Lamivudine as Potential Agents to Combat HIV-Associated Neurocognitive Disorder. Assay Drug Dev Technol. 2019 Oct;17(7):322-329.

Lamivudine is a monothioacetal composed of a cytosine group with a (2R,5S)-2-(hydroxymethyl)-1,3-oxothiacyclopentane-5-yl group attached to the 1-position. It is an HIV-1 reverse transcriptase inhibitor used to treat HIV/AIDS and hepatitis B. Lamivudine has multiple functions, including as an HIV-1 reverse transcriptase inhibitor, antiviral drug, anti-hepatitis B virus drug, allergen, prodrug, and EC 2.7.7.49 (RNA-directed DNA polymerase) inhibitor. It is a monothioacetal, primary alcohol, oxoheterocyclic compound, and nucleoside analog whose function is related to cytosine. Lamivudine (brand name: Epivir) is a prescription drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV infection in adults and children. Lamivudine is often used in combination with other anti-HIV drugs. Lamivudine is a reverse transcriptase inhibitor and an analog of zalcitabine, in which the 3' carbon atom of the pentose ring is replaced by a sulfur atom. It is used to treat human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV) infection. Lamivudine is a nucleoside analog reverse transcriptase inhibitor for both hepatitis B virus and human immunodeficiency virus. Lamivudine's mechanism of action is as a nucleoside reverse transcriptase inhibitor. Lamivudine is a nucleoside analog and reverse transcriptase inhibitor used to treat human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infection. The probability of clinically significant drug-induced liver injury caused by lamivudine is extremely low, but it is associated with potential exacerbation of hepatitis B during treatment or upon abrupt discontinuation. Lamivudine has been reported to be found in Schisandra chinensis and Vitex trifolia, and relevant data are available for reference. Lamivudine is a synthetic nucleoside analog active against both hepatitis B virus (HBV) and HIV. Intracellularly, lamivudine is phosphorylated to its active metabolites, lamivudine triphosphate (L-TP) and lamivudine monophosphate (L-MP). In HIV, L-TP, after incorporation into viral DNA, inhibits HIV-1 reverse transcriptase (RT) via DNA chain termination. In HBV, HBV polymerase incorporates L-MP into viral DNA, leading to DNA chain termination. L-TP has weak inhibitory effects on mammalian DNA polymerases α and β, as well as mitochondrial DNA polymerase. (NCI04)
A reverse transcriptase inhibitor, also a zalcitabine analogue, in which the 3' carbon atom of the pentose ring is replaced by a sulfur atom. Used to treat HIV infection.

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Drug Indications
Used to treat HIV infection and chronic hepatitis B (HBV).
FDA Label
Lamivudine (Teva Pharma BV) is indicated as part of an antiretroviral combination therapy for the treatment of adults and children infected with human immunodeficiency virus (HIV).
Lamivudine (Teva) is indicated for the treatment of adults with chronic hepatitis B who have compensated liver disease with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels, and histological evidence of active liver inflammation and/or fibrosis. Lamivudine treatment should only be considered when alternative antiviral agents with a higher genetic barrier are unavailable or inappropriate (see Section 5.1).
Epivir is indicated as part of an antiretroviral combination therapy for the treatment of adults and children infected with human immunodeficiency virus (HIV).
Zeffix is indicated for the treatment of adults with chronic hepatitis B who have compensated liver disease with active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels, and histological evidence of active liver inflammation and/or fibrosis. Lamivudine treatment should only be considered when alternative antiviral drugs with higher genetic barriers are unavailable or unsuitable; in decompensated liver disease, it should be used in combination with another drug that does not exhibit cross-resistance to lamivudine.
Mechanism of Action
Lamivudine is a synthetic nucleoside analog that is phosphorylated intracellularly to produce its active metabolite, lamivudine triphosphate (L-TP). This nucleoside analog can be incorporated into viral DNA by HIV reverse transcriptase and HBV polymerase, leading to DNA chain termination.
Lamivudine enters cells via passive diffusion and is phosphorylated to produce its active metabolite, lamivudine triphosphate. Lamivudine triphosphate competes with deoxycytidine triphosphate for the binding site of reverse transcriptase, leading to DNA chain termination upon incorporation. Lamivudine has very low affinity for human α and ω DNA polymerases, moderate affinity for β DNA polymerase, and high affinity for γ DNA polymerase. Lamivudine (BCH-189) is a synthetic nucleoside analog of cytidine, belonging to the nucleoside reverse transcriptase inhibitor (NRTI) class [1]. Lamivudine (BCH-189) exerts its antiviral effect by being converted into lamivudine triphosphate in cells. Lamivudine triphosphate competes with deoxycytidine triphosphate (dCTP) for incorporation into viral DNA, thereby terminating DNA chain synthesis [1]. Lamivudine (BCH-189) is indicated for the treatment of chronic hepatitis B virus infection and HIV-1 infection (in combination with other antiretroviral drugs) [1][3]. Lamivudine (BCH-189) shows potential therapeutic potential. Treating HIV-related neurocognitive disorders by reducing neuroinflammation and protecting neurons [3]
Lamivudine (BCH-189) was approved by the FDA in 1998 for the treatment of chronic hepatitis B and by the FDA in 1995 for the treatment of HIV [1]

C8H11N3O3S

229.26

229.052

134678-17-4

Lamivudine salicylate;173522-96-8

60825

White to off-white solid powder

1.7±0.1 g/cm3

475.4±55.0 °C at 760 mmHg

177 °C

241.3±31.5 °C

0.0±2.7 mmHg at 25°C

1.755

-0.71

2

4

2

15

331

2

C1[C@H](O[C@H](S1)CO)N2C=CC(=NC2=O)N

JTEGQNOMFQHVDC-NKWVEPMBSA-N

InChI=1S/C8H11N3O3S/c9-5-1-2-11(8(13)10-5)6-4-15-7(3-12)14-6/h1-2,6-7,12H,3-4H2,(H2,9,10,13)/t6-,7+/m0/s1

4-amino-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (10.90 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 (10.90 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 (10.90 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: 100 mg/mL (436.19 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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