5-HT3 Receptor

Rats treated with dexamethasone and alosetron (1 mg/kg; i.p.; daily for 6 days) had a significantly lower diarrhea index than the TNBS control group, particularly in the first two days of treatment following the induction of colitis.

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The present study was designed to evaluate the anti-inflammatory effect of Alosetron, a 5-HT3R antagonist, on trinitrobenzenesulfonic acid (TNBS)-induced ulcerative colitis in rats. Two h subsequent to induce colitis (intracolonic instillation of TNBS, 50 mg/kg) in male Wistar rats, alosetron (1 mg/kg), dexamethasone (1 mg/kg), meta-chlorophenylbiguanide (mCPBG, a 5-HT3R agonist, 5 mg/kg), or alosetron + mCPBG were administrated intraperitoneally for 6 days. Animals were thereafter sacrificed and the efficacy of drugs was evaluated macroscopically, histologically, and biochemically (myeloperoxidase, tumor necrosis factor-alpha, interleukin-6, and interleukin-1 beta) on distal colon samples. Treatment with alosetron and dexamethasone improved macroscopic and microscopic colonic damages significantly and decreased myeloperoxidase activity and colonic levels of inflammatory cytokines. The profitable effects of alosetron were antagonized by concurrent administration of mCPBG. Our data provided evidence that the protective effects of alosetron on TNBS-induced colitis can be mediated by 5- HT3R. [7]

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Irritable bowel syndrome, which affects 5–10% of the population includes around 25% with predominantly diarrhoea (IBS-D). Several lines of evidence suggest an increase in mucosal 5-HT availability in IBS-D including a decrease in the serotonin transporter (SERT) which is also seen following acute diverticulitis. 5-HT3 receptor antagonists have proved effective in suppressing urgency, prolonging small and large bowel transit and relieving symptoms in IBS-D. Alosetron continues to be used under restricted availability without any serious morbidity despite ischemic colitis which occurs at a rate of <1/1000 patient year. Other agents such as ramosetron and ondansetron are still in use and have not been associated with ischemic colitis. 5-HT3 receptor agonists stimulate intestinal motility, shorten transit times and in a pilot trial accelerated transit in patients with IBS-C. [1]

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Irritable bowel syndrome (IBS) is a highly prevalent functional gastrointestinal disorder that causes a range of symptoms. Currently, Alosetron hydrochloride (Lotronex®), a selective serotonin type 3 receptor antagonist, is the only medication approved for the treatment of severe diarrhea-predominant irritable bowel syndrome (IBS-D) in women who have inadequately responded to conventional therapy. Alosetron has demonstrated efficacy compared with placebo in clinical trials and has been shown to improve overall health-related quality of life (HRQoL). However, rare instances of ischemic colitis and severe complications of constipation have been reported. As a result, in 2000 alosetron was voluntarily withdrawn from the market but was reintroduced in 2002 with a more restricted indication and a requirement that clinicians and patients follow a prescribing program. Although the efficacy and benefit of alosetron has been clearly demonstrated, it has been used sparingly since its reintroduction. This brief review describes the history of Alosetron, efficacy of alosetron in the treatment of IBS, the impact of severe IBS on HRQoL, safety considerations, the risk evaluation and mitigation strategy program under which alosetron is now prescribed, and an update on postmarketing surveillance data. [2]

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Irritable bowel syndrome affects 5-10% of North Americans, with an estimated one-third having a diarrhea-predominant form. Alosetron hydrochloride (Lotronex) is a serotonin receptor type 3 antagonist approved in early 2000 for use in women with diarrhea-predominant irritable bowel syndrome (IBS-D). Initial use was widespread, but infrequent serious adverse events of ischemic colitis and severe constipation-related complications prompted alosetron's voluntary withdrawal from the US market in November 2000. Unprecedented public request prompted its reintroduction in 2002 under a Risk Management Plan, including a more restricted indication and a Prescribing Program for Lotronex. Despite these measures, the use of alosetron has been very limited since its reintroduction. Possible deterrents to its use include concerns over safety and the possible medical-legal implications raised by the Risk Management Plan. It is also possible that changes in the natural history and/or diagnosis of IBS-D have reduced the target population. Given the unique regulatory history of Alosetron, these issues continue to engender controversy. This article profiles these concerns and reviews the pharmacology, clinical efficacy and safety, and post-marketing experience with alosetron. Myths and misconceptions related to alosetron use, or lack thereof, are addressed to provide the reader with the evidence needed to make informed treatment decisions for their female patients with severe IBS-D [3].

Rats were randomly divided into six groups of 6 in each and following treatments were administered: (I) TNBS-control group, rats received normal saline (intraperitoneally, ip) 2 h subsequent to induction of colitis; (II) normal group, animals were administered normal saline intracolonically instead of TNBS; (III) dexamethasone group, dexamethasone (1 mg/kg, ip) was given 2 h following induction of colitis; (IV) Alosetron group, Alosetron (1 mg/kg, ip) was given 2 h following induction of colitis; (V) mCPBG group, mCPBG (5 mg/kg, ip), was administered 2 h following induction of colitis; (VI) Alosetron + mCPBG group, Alosetron and mCPBG were concurrently given (ip) 2 h following induction of colitis. All treatment continued daily for 6 days. [7]

Absorption, Distribution and Excretion
50-60 %
Renal elimination of unchanged alosetron accounts for only 6% of the dose. Alosetron is extensively metabolized in humans.
65 to 95 L
600 mL/min

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Metabolism / Metabolites
Hepatic, via microsomal cytochrome P450 (CYP)
Alosetron has known human metabolites that include 6-Hydroxy-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-3,4-dihydropyrido[4,3-b]indol-1-one and 6-hydroxy-5-methyl-2-[(5-methyl-2-oxo-1,3-dihydroimidazol-4-yl)methyl]-3,4-dihydropyrido[4,3-b]indol-1-one.

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Biological Half-Life
1.5 hours

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of alosetron during breastfeeding. Because of relatively high protein binding and only moderate bioavailability, exposure of the breastfed infant is likely to be low. Until more data are available, alosetron should only be used with careful infant monitoring during breastfeeding.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
82%

[1]. Targeting the 5-HT3 receptor in the treatment of irritable bowel syndrome By Spiller, Robin C. From Current Opinion in Pharmacology (2011), 11(1), 68-74.

[2]. Optimizing outcomes with alosetron hydrochloride in severe diarrhea-predominant irritable bowel syndrome. Therap Adv Gastroenterol. 2010 May;3(3):165-72.

[3]. Alosetron for severe diarrhea-predominant irritable bowel syndrome: safety and efficacy in perspective. Expert Rev Gastroenterol Hepatol. 2010 Feb;4(1):13-29.

[4]. Acute hepatitis associated with alosetron (Lotronex). J Clin Gastroenterol. 2005 Aug;39(7):641-2.

[5]. Incidence of colonic ischemia, hospitalized complications of constipation, and bowel surgery in relation to use of alosetron hydrochloride. Am J Gastroenterol. 2003 May;98(5):1117-22.

[6]. Alosetron. Drugs. 2000;59(3):511-520.

[7]. Anti-inflammatory effects of alosetron mediated through 5-HT3 receptors on experimental colitis. Res Pharm Sci. 2019;14(3):228-236.

Alosetron is a pyrido[4,3-b]indole compound having a 5-methyl-1H-imidazol-4-ylmethyl group at the 2-position. It has a role as a serotonergic antagonist, an antiemetic and a gastrointestinal drug. It is a pyridoindole and a member of imidazoles.
Alosetron is a 5-HT3 antagonist used only for the management of severe diarrhoea-predominant irritable bowel syndrome (IBS) in women. Alosetron has an antagonist action on the 5-HT3 receptors and thus may modulate serotonin-sensitive gastrointestinal (GI) processes. Alosetron was voluntarily withdrawn from the US market in November 2000 by the manufacturer due to numerous reports of severe adverse effects including ischemic colitis, severely obstructed or ruptured bowel, and death. In June 2002, the FDA approved a supplemental new drug application allowing the remarketing of the drug under restricted conditions of use.
Alosetron is a Serotonin-3 Receptor Antagonist. The mechanism of action of alosetron is as a Serotonin 3 Receptor Antagonist.
Alosetron is a potent and selective 5-HT3 receptor antagonist. Alosetron blocks the actions of serotonin at 5-HT3 sites in the peripheral nervous system, particularly on enteric and nociceptive sensory neurons, thereby affecting the regulation of visceral pain, decreasing gastrointestinal contraction and motility, and decreasing gastrointestinal secretions. This agent is used to treat diarrhea-predominant irritable bowel syndrome in women.
See also: Alosetron Hydrochloride (has salt form).

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Drug Indication
Only for the treatment of symptoms of severe diarrhea-predominant irritable bowel syndrome (IBS) in women with chronic symptoms (generally lasting greater than 6 months) who does not present with anatomic or biochemical GI abnormalities and have not responded to conventional therapy.
FDA Label

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Mechanism of Action
Alosetron is a potent and selective 5-HT₃ receptor antagonist. 5-HT₃ receptors are nonselective cation channels that are extensively distributed on enteric neurons in the human gastrointestinal tract, as well as other peripheral and central locations. Activation of these channels and the resulting neuronal depolarization affect the regulation of visceral pain, colonic transit and gastrointestinal secretions, processes that relate to the pathophysiology of irritable bowel syndrome (IBS). 5-HT₃ receptor antagonists such as alosetron inhibit activation of non-selective cation channels which results in the modulation of serotonin-sensitive GI motor and sensory processes.

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Pharmacodynamics
Alosetron is a potent and selective antagonist of the serotonin 5-HT₃ receptor type. Activation of these receptors and the resulting neuronal depolarization affects the regulation of visceral pain, colonic transit, and GI secretions processes that are related to IBS. By blocking these receptors, alosetron is able to effectively control IBS.

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Alosetron Hydrochloride is the hydrochloride salt form of alosetron, a potent and selective 5-HT3 receptor antagonist. Alosetron blocks the actions of serotonin at 5-HT3 sites in the peripheral nervous system, particularly on enteric and nociceptive sensory neurons, thereby affecting the regulation of visceral pain, decreasing gastrointestinal contraction and motility, and decreasing gastrointestinal secretions. This agent is used to treat diarrhea-predominant irritable bowel syndrome in women.
See also: Alosetron (has active moiety).

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Mechanism of Action
Serotonin 5HT3-receptor antagonist /Salt not specified/
... 5-HT3 antagonists delay colonic transit, incr colonic compliance, & incr small intestinal water absorption. ... /Salt not specified/
Alosetron (Lotronex) is a potent, highly selective 5-HT(3) antagonist. ...

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Alosetron Hydrochloride is the hydrochloride salt form of alosetron, a potent and selective 5-HT3 receptor antagonist. Alosetron blocks the actions of serotonin at 5-HT3 sites in the peripheral nervous system, particularly on enteric and nociceptive sensory neurons, thereby affecting the regulation of visceral pain, decreasing gastrointestinal contraction and motility, and decreasing gastrointestinal secretions. This agent is used to treat diarrhea-predominant irritable bowel syndrome in women.
ALOSETRON HYDROCHLORIDE is a small molecule drug with a maximum clinical trial phase of IV that was first approved in 2000 and is indicated for irritable bowel syndrome. This drug has a black box warning from the FDA.

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Drugs acting at 5-HT3 receptor alter gut transit with agonists accelerating and antagonists slowing gut transit. All 5-HT3 receptor antagonists improve symptoms in IBS-D but have constipation as a side effect with alosetron > cilansetron > ramosetron > ondansetron. While both Alosetron and cilansetron have been associated with ischemic colitis this has not been reported with either ramosetron or ondansetron. The principle of using such drugs in IBS-D remains sound and benefits for patients with severe IBS-D and marked impairment of quality of life justify the small risks of ischemic colitis, which resolves rapidly on discontinuing the drug. The original doses recommended may well have been excessive and careful dose titration starting with very low doses may well avoid severe side effects in the future. Pilot studies suggest 5-HT3 receptor agonists benefit patients with constipation but larger studies are needed to be confident of the risk/benefit ratio. [1]

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Alosetron hydrochloride (Lotronex, GlaxoSmithKline, Inc) is a safe and effective agent for selective patients with severe irritable bowel syndrome when prescribed as recommended. We describe the first reported case of acute liver injury in a 39-year-old white woman who developed symptomatic hepatitis 28 days after starting alosetron. All other competing causes of acute hepatitis were excluded by radiologic and laboratory studies and the liver injury resolved after drug discontinuation. Although the mechanism of alosetron hepatotoxicity is unknown, metabolic idiosyncrasy is suspected since the drug is known to be extensively metabolized by cytochrome-P450 enzymes. Clinicians prescribing alosetron should be aware of this potential side effect if unexplained abdominal pain, jaundice,or abnormal liver biochemistries are encountered in a treated patient.[4]

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Objective: Alosetron hydrochloride (Lotronex), a potent selective 5-hydroxytryptamine(3) receptor antagonist, was approved in February, 2000 in the United States for the treatment of diarrhea-predominant irritable bowel syndrome (IBS) in women. Marketing was suspended in November, 2000, after reports of colonic ischemia and serious complications of constipation. We sought to compare the incidence of colonic ischemia, hospitalized complications of constip
ation, and bowel surgery among alosetron users and a cohort of patients with IBS who did not use alosetron. Methods: We sought outcomes of colonic ischemia, hospitalized complications of constipation, and bowel surgery in 3,631 Lotronex users and 2,480 comparison IBS subjects using diagnoses, procedures, and drugs recorded in the UnitedHealthcare insurance claims database, and validated these by chart review. The initial assessment was to last for 3 yr beginning with the start of Alosetron treatment and was to include 10,000 Lotronex users; however, the observation period ended by December 31, 2000, after suspension of marketing.
Results: There were 3631 Alosetron users among members of UnitedHealthcare from March through December, 2000, and we identified 2480 comparison IBS-only patients; follow-up time averaged about 5 months in both groups. There were no instances of colonic ischemia in either cohort. Thirty instances of bowel surgery occurred, giving rates of 10.2/1000 person-yr in the alosetron cohort and 11.8/1000 person-yr in the IBS/no alosetron cohort. There were three cases of hospitalized complications of constipation. The incidence rates were essentially the same in alosetron users (1.24/1000 person-yr) and in IBS patients with no alosetron use (0.92/1000 person-yr).
Conclusions: Alosetron users did not differ from IBS patients not using alosetron in the incidence of bowel surgery or hospitalized complications of constipation; there were no cases of colonic ischemia. The statistical upper limit of colonic ischemia rates in alosetron users was 2.28/1000 person-yr. Because of the market withdrawal, the size of the cohort and the duration of follow-up were smaller than originally planned; consequently, the statements about the safety of alosetron were necessarily limited. On June 7, 2002, the Food and Drug Administration approved alosetron for reintroduction in the U.S. market for women with severe diarrhea-related IBS.[5]

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Alosetron is a potent and highly selective serotonin 5-HT3 receptor antagonist which has been evaluated for the management of irritable bowel syndrome (IBS). It blocked the fast 5HT3-mediated depolarisation of guinea-pig myenteric and submucosal neurons in vitro, with half-maximal inhibition at approximately 55 nmol/L. Alosetron attenuated the visceral nociceptive effect of rectal distension in conscious or anaesthetised dogs. It increased the compliance of the colon to distension in patients with IBS and delayed colonic transit in patients with IBS or carcinoid diarrhoea and in healthy volunteers. A single dose of alosetron 4 mg increased in vivo fluid absorption in normal human small intestine. In clinical trials in patients with IBS, alosetron 1 mg twice daily was effective in relieving abdominal pain and discomfort. Alosetron was most effective in female patients and particularly in those with diarrhoea-predominant IBS. In patients with IBS and healthy volunteers who received alosetron, the most common adverse event was constipation.[6]

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To draw a conclusion, this study suggests that Alosetron, as a 5-HT3R antagonist, attenuated the severity of TNBS-induced colitis. Alosetron exerted a positive effect upon colonic injuries, neutrophil infiltration, and corresponding pro-inflammatory mediators. Additionally, the anti-nociceptive effect of alosetron on IBS has been well documented. Despite the fact that ischemic colitis is the most deleterious side effect of alosetron in IBS patients, its incidence is extremely low. In addition, if ischemic colitis occurred during the experiment, we would expect deterioration in histological and biochemical injuries of colitis. In this regard, further studies are required to establish whether ischemic colitis also occurs as a consequence of administration of alosetron in animal models of UC. Based on our findings, alosetron may find a place in the therapy of IBD in future, but complementary studies are recommended.
CONCLUSION: Taken together, it is concluded that Alosetron exerted anti-inflammatroy effect on TNBS model of experimental colitis, despite the concerns about its ischemic colitis induction as a troublesome adverse effect and this activity was mediated through 5-HT3 receptors. Hence, subsequent clinical studies are required to evaluate its efficacy, safety, and suitability in human IBD conditions.[7]

C17H18N4O

294.35102

294.148

C, 69.37; H, 6.16; N, 19.03; O, 5.44

122852-42-0

Alosetron Hydrochloride;122852-69-1;Alosetron-d3 hydrochloride;1189919-71-8;Alosetron (Hydrochloride(1:X));132414-02-9;Alosetron-d3;1190043-13-0;Alosetron ((Z)-2-butenedioate);122852-43-1

2099

Typically exists as solid at room temperature

1.34 g/cm3

648.1ºC at 760 mmHg

345.8ºC

1.1E-16mmHg at 25°C

1.706

2.346

1

2

2

22

442

0

O=C(C(C1=C2C=CC=C1)=C(N2C)CC3)N3CC4=C(NC=N4)C

JSWZEAMFRNKZNL-UHFFFAOYSA-N

InChI=1S/C17H18N4O/c1-11-13(19-10-18-11)9-21-8-7-15-16(17(21)22)12-5-3-4-6-14(12)20(15)2/h3-6,10H,7-9H2,1-2H3,(H,18,19)

5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-3,4-dihydropyrido[4,3-b]indol-1-one

alosetron; 122852-42-0; CHEBI:253342; UNII-13Z9HTH115; A03AE01; 13Z9HTH115; 1H-Pyrido(4,3-b)indol-1-one, 2,3,4,5-tetrahydro-5-methyl-2-((5-methyl-1H-imidazol-4-yl)methyl)-; 2,3,4,5-Tetrahydro-5-methyl-2-((5-methyl-1H-imidazol-4-yl)methyl)-1H-pyrido(4,3-b)indol-1-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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

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.)