VEGFR2 (IC50 = 0.2 nM); VEGFR3 (IC50 = 0.7 nM); c-Kit (IC50 = 14.8 nM); c-Kit (IC50 = 14.8 nM); c-Kit (IC50 = 14.8 nM)

After a 29-day treatment cycle, daily oral administration of anlotinib (5 mg/kg) resulted in a complete response in 55% of treated animals and in a reduced tumor volume and tumor weights of AN3CA tumors by 94% and 96%, respectively. While paclitaxel and carboplatin were unable to stop the growth of the tumor, their combination with anlotinib did not appear to have a better result than Anlotinib treatment alone.

Anlotinib (formerly known as AL3818) is a novel and powerful multi-kinase inhibitor that blocks Ret, FGFR1-4, PDGFRα/β, c-Kit, and VEGFR2/3.

Inhibitory activity of anlotinib against tyrosine kinases was determined using ELISA, as described previously.22 Reaction of ATP with tyrosine kinase was initiated in reaction buffer (50 mmol/L HEPES pH 7.4, 50 mmol/L MgCl2, 0.5 mmol/L MnCl2, 0.2 mmol/L Na3VO4, 1 mmol/L DTT) and incubated for 1 hour at 37°C in 96‐well plates precoated with 20 μg/mL Poly(Glu,Tyr)4:1. The plate was incubated with PY99 antibody and then with HRP‐conjugated anti‐mouse IgG. After reaction with o‐phenylenediamine solution and then termination with the addition of 2N H2SO4, absorbance was measured at 490 nm using a Synergy H4 Hybrid reader[3].

In vitro, AL3818 dramatically lowers the number of AN3CA cells, which are identified by the high expression of a mutant FGFR2 protein. After a 29-day treatment cycle, daily oral administration of AL3818 (5 mg/kg) resulted in a complete response in 55% of treated animals and in a reduction of tumor volume and tumor weights of AN3CA tumors by 94% and 96%, respectively. When compared to AL3818 treatment alone, the combination of carboplatin and paclitaxel did not appear to have a greater effect, despite their inability to change the growth of the tumor.

human colon cancer SW620 xenograft model（Balb/cA-nude mice, 5-6 weeks old)
0.75, 1.5, 3 and 6 mg/kg
oral

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Female nude mice (Balb/cA‐nude, 5‐6 weeks old), purchased from Shanghai Laboratory Animal Center (Chinese Academy of Sciences, Shanghai, China), were housed in sterile cages under laminar airflow hoods in a specific pathogen‐free room with a 12‐hour light/12‐hour dark schedule, and fed autoclaved chow and water ad libitum. Human tumor xenografts were established by s.c. inoculating cells into the left axilla of nude mice. When tumor volumes reached 100‐200 mm3, mice were divided randomly into control and treatment groups. Control groups were given vehicle alone, and treatment groups received oral anlotinib or sunitinib daily. Tumor volume was calculated as (length × width2)/2. Tumor growth inhibition was calculated from the start of treatment by comparing changes in tumor volumes for control and treatment groups.[1]

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Rat studies[3]
Rats were randomly assigned to four groups (five male and five female rats per group) to receive a single oral dose of anlotinib at 1.5, 3, or 6 mg/kg (via gavage) or a single intravenous dose at 1.5 mg/kg (from the tail vein). Serial blood samples (around 0.25 mL; before and 5, 15, and 30 min and 1, 2, 4, 6, 8, 11, and 24 h after dosing) were collected in heparinized tubes from the orbital sinuses of rats under isoflurane anesthesia and centrifuged at 1300×g for 10 min to yield plasma fractions. Rats under isoflurane anesthesia were killed by bleeding from the abdominal aorta at 1, 4, 8, and 24 h (three male and three female rats per time point) after a single oral dose of anlotinib at 3 mg/kg. [3]

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Tumor-bearing mouse studies[3]
Female tumor-bearing mice were randomly assigned to three groups (20 mice per group) to receive a single oral dose of anlotinib at 0.75, 1.5, or 3 mg/kg (via gavage). Mice under isoflurane anesthesia were killed by bleeding from the orbital sinus at 2, 4, 8, and 24 h (five mice per time point) after dosing.

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Dog study[3]
Dogs were randomly assigned to four groups (three male and three female dogs per group) to receive a single oral dose of anlotinib at 0.5, 1, or 2 mg/kg (via gavage) or a single intravenous dose at 0.5 mg/kg (from left forelimb vein).

Plasma pharmacokinetics of anlotinib in rats and in dogs [3]
Mean plasma concentrations of anlotinib over time after a single dose of anlotinib in rats and dogs are shown in Figure 1; the plasma pharmacokinetic parameters of anlotinib are summarized in Table 1. After oral administration, levels of systemic exposure to anlotinib, i.e., plasma maximum concentration (Cmax) and area under the plasma concentration-time curve up to 24 h (AUC0-24 h), in female rats tended to be greater than those in male rats at the tested dose range 1.5–6 mg/kg, while gender differences in plasma Cmax and AUC0-24 h of anlotinib were not significant in dogs at the dose range 0.5–2 mg/kg. The plasma Cmax and AUC0-24h increased as the anlotinib dose increased in an over-proportional manner in rats and dogs (Table 2). Anlotinib was highly bound in rat, dog, and human plasma with unbound fractions in plasma (fu) of 2.9%, 4.0%, and 7.3%, respectively. These fu values were independent of total plasma concentration of anlotinib, suggesting that such total concentration of anlotinib is a good measure of the changes in its unbound concentration in plasma for the species. As shown in Table 3, anlotinib exhibited binding affinity for α1-acid glycoprotein similar to imatinib, another tyrosine kinase inhibitor. However, it exhibited substantially higher affinity for albumin than imatinib. Unlike imatinib with an nKα1-acid-glycoprotein/nKalbumin ratio of 92.0, such a ratio for anlotinib was 0.9 (<7.7), suggesting the high excess of plasma concentration of albumin (600 μmol/L) over α1-acid glycoprotein (20 μmol/L) could not be compensated for circulating anlotinib in humans. It is worth mentioning that anlotinib exhibited notably higher affinity for plasma lipoproteins, particularly for low density lipoproteins and very low density lipoproteins, than for albumin and α1-acid glycoprotein. After oral administration, anlotinib was rapidly absorbed from the gastrointestinal tract in rats and dogs (Figure 1). Dogs tended to exhibit greater oral bioavailability (F) of anlotinib than rats. Terminal half-lives (t1/2) of anlotinib in rats and dogs after intravenous administration were comparable with the respective t1/2 values after oral administration. Dogs exhibited a longer mean t1/2 of anlotinib than rats. This t1/2 difference appeared to be attributed mainly to interspecies difference in total plasma clearance (CLtot,p). Anlotinib's mean apparent volume of distribution at steady state (VSS) in rats was 40 times as much as the rat volume of total body water and the value of VSS in dogs was 12 times as much as the dog volume of total body water15, suggesting the compound was distributed widely into various body fluids and tissues. In rats that received an intravenous dose of anlonitib, only small amounts of the unchanged compound were excreted into urine, bile, and feces (Table 1), suggesting that metabolism was the major elimination route of anlotinib.

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Intestinal absorption-related properties of anlotinib [3]
Intestinal absorption of a drug is a combined result of its solubility in gastrointestinal fluids, membrane permeability, and substrate specificity to efflux system of the intestinal epithelia. Anlotinib exhibited pH-dependent aqueous solubility, ie, >1 g/mL at pH 1.7 (the stomach), 114 μg/mL at pH 4.6 (the duodenum), and 0.89 μg/mL at pH 6.5 (the jejunum and the ileum). The solubility values of anlotinib at pH 1.7 and 4.6 were greater than the compound's minimum solubility necessary to achieve adequate intestinal absorption at the dose 6 mg/kg, but the solubility value at pH 6.5 was lower than the minimum solubility. The minimum solubility was deduced according to a bar chart, by Lipinski, that depicts the minimum solubility for compounds with low, medium, and high permeability at doses of 0.1, 1, and 10 mg/kg16. Anlotinib exhibited good membrane permeability across Caco-2 cell monolayers, expressing MDR1, MRP2, and BCRP, with a mean apparent permeability coefficient (Papp) of 3.5×10−6 cm/s. The compound exhibited a mean efflux ratio (EfR) of 0.91±0.22, suggesting that its transport across the cell monolayer did not affected by the apical efflux transporters in Caco-2 cells (Supplementary Figure S1). Physicochemical properties of anlotinib (predicted using ACD/Percepta; Toronto, Ontario, Canada), ie, molecular mass (407 Da; favorable value, <500 Da), hydrogen-bonding capacity (HBA+HBD, 6+3; <12), topological polar surface area (TPSA, 82.4 Å2; <140 Å2), and molecular flexibility (NROTB, 6; <10), supported its good membrane permeability. Measured LogD values were −0.89 at pH 1.7, 2.10 at pH 4.6, and 2.38 at pH 6.5 (favorable range, 0–5).

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Tissue distribution of anlotinib in rats and tumor-bearing mice [3]
Levels of various tissue exposures to anlotinib (measured using associated tissue homogenate samples) in rats and tumor-bearing mice after an oral dose of the compound were significantly higher than the associated systemic exposure level (Figure 2). In rats, the lung exhibited the highest exposure level, which was 197 times as high as the systemic exposure level. Meanwhile, the rat liver, kidneys, and heart also exhibited high exposure levels, which were 49, 54, and 32 times as much as the systemic exposure level. Anlotinib penetrated the rat brain, with a brain homogenate AUC0-24h level comparable to the associated plasma level. In tumor-bearing mice, the level of tumor tissue exposure to the compound increased as the dose increased; it was 13 times as high as the systemic exposure level.

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Metabolism of anlotinib [3]
Because neither hepatobiliary nor renal excretion of unchanged compound was the main elimination route, metabolites of anlotinib in rat and dog samples were detected and characterized. As a result, a total of 12 anlotinib metabolites (M1–M12) were detected in the plasma, bile, urine, and feces samples of rats after dosing (Table 4). Eight of the metabolites, ie, M2, M4, M5, M6, M8, M9, M10, and M11, were found in plasma. All these metabolites occurred in rat bile and urine samples, except for M7 and M11, which occurred only in rat bile samples. In dogs, a total of 5 metabolites of anlotinib were detected in plasma samples; they were M4, M8, M9, M10, and M11. After liquid chromatography/mass spectrometry-based characterization of these metabolites, metabolic pathways of anlotinib were proposed (Figure 3). The major metabolic pathways of anlotinib in rats were probably the hydroxylation to form M10 and M11 and the dealkylation to form M8. The metabolites M10 and M11 were two major plasma metabolites of anlotinib in rats, while M8 was further glucuronized to form M6, a major plasma and biliary metabolite of anlotinib. To further characterize these metabolic pathways, in vitro metabolism studies were performed for anlotinib. As a result, multiple human cytochrome P450 enzymes, ie, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5, were found to be able to mediate the oxidation of anlotinib to form M10, M11, and M8 (Figure 4A). Among these enzymes were CYP3A4 and CYP3A5 that exhibited the greatest metabolic capabilities. As shown in Figure 4B, the metabolites M10, M11, and M8 were also detected in samples of anlotinib after being incubated with NADPH-fortified rat liver microsomes, dog liver microsomes, and human liver microsomes under the same conditions. The total amounts of metabolites formed were different for the tested liver microsomes of different species, suggesting the highest oxidation rate by rat liver microsomes followed by dog liver microsomes, and then by human liver microsomes.

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In vitro inhibitory activity of anlotinib on drug metabolism enzymes and transporters [3]
As shown in Table 5, anlotinib exhibited, in vitro, significant potency to inhibit CYP3A4 and CYP2C9 with IC50 values of <1 μmol/L; such inhibitory potency towards CYP2C19, CYP2C8, UGT1A1, UGT1A4, UGT1A9, and UGT2B15 was moderate, with IC50 values of 1–10 μmol/L. This tyrosine kinase inhibitor exhibited low inhibitory potency in vitro towards human CYP2B6, CYP2D6, UGT1A6, UGT2B7, OATP1B1, OAT3, OCT2, MDR1, and BCRP with values of IC50 greater than 10 μmol/L. No significant inhibitory potency of anlotinib was found towards human CYP1A2, CYP3A5, OATP1B3, OAT1, and MRP1. Anlotinib was not an in vitro substrate of OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MDR1, and BCRP (Supplementary Table S1).

On the 4/0 schedule, no DLT was observed in the first four patients at the starting dose of 5 mg/day. However, at 10 mg/day, one patient developed grade 3 hypertension among the first three patients treated. An additional patient was enrolled and also developed grade 3 hypertension. Therefore, the further dose escalation was halted. Meanwhile, PK study revealed a continuously significant anlotinib accumulation in patients who received continuous administration (data not shown). Based on the PK profile of anlotinib and the two DLTs observed at the dose of 10 mg/day, we modified the administration protocol from the 4/0 schedule to the 2/1.[2]
On the 2/1 schedule, because none of the three patients experienced DLT at initial doses of 10 mg/day, the dose escalation proceeded to 16 mg/day. Two of the three patients in the 16 mg cohort experienced DLT (one grade 3 fatigue and one grade 3 hypertension). Therefore, the MTD had been exceeded, and the next lower dose of 12 mg/day was further evaluated by entering additional patients. None of the initial three patients experienced grade 3/4 adverse events. On the basis, 12 mg once daily was selected for the expanding study. [2]
A total of 21 patients received the 12 mg/day dose on the 2/1 schedule. During the first 2 cycles, all the patients experienced an adverse event of any causality. All the hematologic toxicities were mild. As illustrated in Table 2, the most common non-hematologic adverse events were hypothyroidism, triglyceride elevation, total cholesterol elevation, ALT elevation, diarrhea, and proteinuria. During the first 2 cycles, a total of two patients (10 %) experienced grade 3 adverse events (one triglyceride elevation and one lipase elevation). During all treatment cycles, there were six patients (29 %) with grade 3/4 adverse events. The most common (>5 %) non-hematologic grade 3 adverse events were hypertension, triglyceride elevation, hand-foot skin reaction, and lipase elevation.

[1]. Cancer Sci . 2018 Apr;109(4):1207-1219.

[2]. J Hematol Oncol . 2016 Oct 4;9(1):105.

[3]. Acta Pharmacol Sin . 2018 Jun;39(6):1048-1063.

Anlotinib has been investigated for the treatment of Non-small Cell Lung Cancer and Metastatic Colorectal Cancer.
Catequentinib is a receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic and anti-angiogenic activities. Upon administration, catequentinib targets multiple RTKs, including vascular endothelial growth factor receptor type 2 (VEGFR2) and type 3 (VEGFR3). This agent may both inhibit angiogenesis and halt tumor cell growth.

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Drug Indication
Treatment of Ewing sarcoma, Treatment of soft tissue sarcomas

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Catequentinib Hydrochloride is the hydrochloride salt form of catequentinib, a receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic and anti-angiogenic activities. Upon administration, catequentinib targets multiple RTKs, including vascular endothelial growth factor receptor type 2 (VEGFR2) and type 3 (VEGFR3). This agent may both inhibit angiogenesis and halt tumor cell growth.

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brogating tumor angiogenesis by inhibiting vascular endothelial growth factor receptor-2 (VEGFR2) has been established as a therapeutic strategy for treating cancer. However, because of their low selectivity, most small molecule inhibitors of VEGFR2 tyrosine kinase show unexpected adverse effects and limited anticancer efficacy. In the present study, we detailed the pharmacological properties of anlotinib, a highly potent and selective VEGFR2 inhibitor, in preclinical models. Anlotinib occupied the ATP-binding pocket of VEGFR2 tyrosine kinase and showed high selectivity and inhibitory potency (IC50 <1 nmol/L) for VEGFR2 relative to other tyrosine kinases. Concordant with this activity, anlotinib inhibited VEGF-induced signaling and cell proliferation in HUVEC with picomolar IC50 values. However, micromolar concentrations of anlotinib were required to inhibit tumor cell proliferation directly in vitro. Anlotinib significantly inhibited HUVEC migration and tube formation; it also inhibited microvessel growth from explants of rat aorta in vitro and decreased vascular density in tumor tissue in vivo. Compared with the well-known tyrosine kinase inhibitor sunitinib, once-daily oral dose of anlotinib showed broader and stronger in vivo antitumor efficacy and, in some models, caused tumor regression in nude mice. Collectively, these results indicate that anlotinib is a well-tolerated, orally active VEGFR2 inhibitor that targets angiogenesis in tumor growth, and support ongoing clinical evaluation of anlotinib for a variety of malignancies.[1]

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Background: Anlotinib is a novel multi-target tyrosine kinase inhibitor that is designed to primarily inhibit VEGFR2/3, FGFR1-4, PDGFR α/β, c-Kit, and Ret. We aimed to evaluate the safety, pharmacokinetics, and antitumor activity of anlotinib in patients with advanced refractory solid tumors. Methods: Anlotinib (5-16 mg) was orally administered in patients with solid tumor once a day on two schedules: (1) four consecutive weeks (4/0) or (2) 2-week on/1-week off (2/1). Pharmacokinetic sampling was performed in all patients. Twenty-one patients were further enrolled in an expanded cohort study on the recommended dose and schedule. Preliminary tumor response was also assessed. Results: On the 4/0 schedule, dose-limiting toxicity (DLT) was grade 3 hypertension at 10 mg. On the 2/1 schedule, DLT was grade 3 hypertension and grade 3 fatigue at 16 mg. Pharmacokinetic assessment indicated that anlotinib had long elimination half-lives and significant accumulation during multiple oral doses. The 2/1 schedule was selected, with 12 mg once daily as the maximum tolerated dose for the expanding study. Twenty of the 21 patients (with colon adenocarcinoma, non-small cell lung cancer, renal clear cell cancer, medullary thyroid carcinoma, and soft tissue sarcoma) were assessable for antitumor activity of anlotinib: 3 patients had partial response, 14 patients had stable disease including 12 tumor burden shrinkage, and 3 had disease progression. The main serious adverse effects were hypertension, triglyceride elevation, hand-foot skin reaction, and lipase elevation. Conclusions: At the dose of 12 mg once daily at the 2/1 schedule, anlotinib displayed manageable toxicity, long circulation, and broad-spectrum antitumor potential, justifying the conduct of further studies.[2]

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Anlotinib is a new oral tyrosine kinase inhibitor; this study was designed to characterize its pharmacokinetics and disposition. Anlotinib was evaluated in rats, tumor-bearing mice, and dogs and also assessed in vitro to characterize its pharmacokinetics and disposition and drug interaction potential. Samples were analyzed by liquid chromatography/mass spectrometry. Anlotinib, having good membrane permeability, was rapidly absorbed with oral bioavailability of 28%-58% in rats and 41%-77% in dogs. Terminal half-life of anlotinib in dogs (22.8±11.0 h) was longer than that in rats (5.1±1.6 h). This difference appeared to be mainly associated with an interspecies difference in total plasma clearance (rats, 5.35±1.31 L·h-1·kg-1; dogs, 0.40±0.06 L·h-1/kg-1). Cytochrome P450-mediated metabolism was probably the major elimination pathway. Human CYP3A had the greatest metabolic capability with other human P450s playing minor roles. Anlotinib exhibited large apparent volumes of distribution in rats (27.6±3.1 L/kg) and dogs (6.6±2.5 L/kg) and was highly bound in rat (97%), dog (96%), and human plasma (93%). In human plasma, anlotinib was predominantly bound to albumin and lipoproteins, rather than to α1-acid glycoprotein or γ-globulins. Concentrations of anlotinib in various tissue homogenates of rat and in those of tumor-bearing mouse were significantly higher than the associated plasma concentrations. Anlotinib exhibited limited in vitro potency to inhibit many human P450s, UDP-glucuronosyltransferases, and transporters, except for CYP3A4 and CYP2C9 (in vitro half maximum inhibitory concentrations, <1 μmol/L). Based on early reported human pharmacokinetics, drug interaction indices were 0.16 for CYP3A4 and 0.02 for CYP2C9, suggesting that anlotinib had a low propensity to precipitate drug interactions on these enzymes. Anlotinib exhibits many pharmacokinetic characteristics similar to other tyrosine kinase inhibitors, except for terminal half-life, interactions with drug metabolizing enzymes and transporters, and plasma protein binding.[3]

C23H22FN3O3

407.45

407.16

C, 67.80; H, 5.44; F, 4.66; N, 10.31; O, 11.78

1058156-90-3

1058156-90-3;1360460-82-7 (HCl);

25017411

Solid powder

3.7

2

6

6

30

606

0

CC1=CC2=C(N1)C=CC(=C2F)OC3=C4C=C(C(=CC4=NC=C3)OCC5(CC5)N)OC

KSMZEXLVHXZPEF-UHFFFAOYSA-N

InChI=1S/C23H22FN3O3/c1-13-9-15-16(27-13)3-4-19(22(15)24)30-18-5-8-26-17-11-21(20(28-2)10-14(17)18)29-12-23(25)6-7-23/h3-5,8-11,27H,6-7,12,25H2,1-2H3

1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinolin-7-yl]oxymethyl]cyclopropan-1-amine

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)

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.)