Absorption, Distribution and Excretion
Gastrointestinal absorption of inositol hexanicotinate varies widely, with an average of 70% of an orally ingested dose absorbed from stomach and upper small intestines into the bloodstream as intact form. The maximum serum levels of nicotinic acid is reached approximately 6-10 hours after oral ingestion. At low concentrations, the absorption of nicotinic acid and nicotinamide is mediated by sodium ion-dependent facilitated diffusion. At higher concentrations, passive diffusion predominates with doses of 3 to 4 g of niacin being almost completely absorbed.
Unabsorbed inositol nicotinate is detected in feces.
Mean Vd following intravenous administration of 50mg/kg of inositol nicotinate in rats is 1051±250 mL/kg.
Mean clearance rate following intravenous administration of 50mg/kg of inositol nicotinate in rats is 65.4±19 mL/min/kg.

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Metabolism / Metabolites
Inositol nicotinate undergoes hydrolysis by plasma esterases, releasing free nicotinic acid and inositol in a sustained manner. The process takes more than 48hours, where the bloodstream enzymatic hydrolysis of inositol hexanicotinate was found to be slower in the first ester linkage of inositol hexanicotinate than in subsequent linkages. Sequential hydrolytic steps of inositol nicotinate forms one nicotinic acid molecule in each step, producing eventually six molecules of nicotinic acid and one inositol moiety.

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Biological Half-Life
Mean elimination half life in healthy human adults is approximately one hour.

[1]. A systematic review and economic evaluation of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease. NIHR Health Technology Assessment programme: Executive Summaries.

Inositol hexanicotinate is an inositol nicotinate. It is functionally related to a nicotinic acid.
Inositol nicotinate, also known as Inositol hexaniacinate/hexanicotinate or "no-flush niacin", is a niacin ester and vasodilator. It is used in food supplements as a source of niacin (vitamin B3), where hydrolysis of 1 g (1.23 mmol) inositol hexanicotinate yields 0.91 g nicotinic acid and 0.22 g inositol. Niacin exists in different forms including nicotinic acid, nicotinamide and other derivatives such as inositol nicotinate. It is associated with reduced flushing compared to other vasodilators by being broken down into the metabolites and inositol at a slower rate. Nicotinic acid plays an essential role in many important metabolic processes and has been used as lipid-lowering agent. Inositol nicotinate is prescribed in Europe under the name Hexopal as a symptomatic treatment for severe intermittent claudication and Raynaud’s phenomenon.
Inositol Niacinate is a niacin formulation that contains no free niacin, but can be hydrolyzed to release free niacin in vivo. Use of inositol niacinate is associated with less flushing than that seen with the use of free niacin.

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Drug Indication
Indicated as a dietary supplement for the source of niacin. Has been investigated for potential beneficial effects on serum lipids. In Europe, inositol hexanicotinate is indicated as a patented drug known as Hexopal, which is therapeutically indicated for the symptomatic relief of severe intermittent claudication and Raynaud’s phenomenon.

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Mechanism of Action
Inositol nicotinate and other niacins directly and noncompetitively inhibit microsomal enzyme diacylglycerol acyltransferase 2 (DGAT2) responsible for esterification of fatty acids to form triglycerides, resulting in decreased triglyceride synthesis and hepatic atherogenic lipoprotein secretion. Inhibitied triglyceride synthesis results in accelerated intracellular hepatic apo B degradation and the decreased secretion of VLDL and LDL particles. Niacin also inhibits hepatic expression of beta-chain adenosine triphosphate synthase which inhibits the removal or uptake of HDL–apo A-I. It is also suggested that niacin increases vascular endothelial cell redox state, resulting in the inhibition of oxidative stress and vascular inflammatory genes or key cytokines involved in atherosclerosis. It acts as a ligand on G-protein coupled receptor 109A (HCAR2/HM74A) and 109B (HCAR3/HM74) which mediates the anti-lipolytic and lipid-lowering effects of nicotinic acid. Niacin-mediated signalling of GPR109A expressed on adipocytes and G(i)-mediated decrease in cAMP levels result in decreased lipolysis, fatty acid mobilization, and triglyceride synthesis. The action of inositol nicotinate on GPR109A expressed on skin and macrophages to cause increased prostaglandin D2/E2 activity is thought to be less significant compared to other niacin molecules as it involves sustained release that leads to less flushing.

C42H30N6O12

810.73

810.192

6556-11-2

3720

White to off-white solid powder

1.5±0.1 g/cm3

897.0±65.0 °C at 760 mmHg

254-256ºC

496.3±34.3 °C

0.0±0.3 mmHg at 25°C

1.675

6.37

0

18

18

60

1210

0

MFZCIDXOLLEMOO-UHFFFAOYSA-N

InChI=1S/C42H30N6O12/c49-37(25-7-1-13-43-19-25)55-31-32(56-38(50)26-8-2-14-44-20-26)34(58-40(52)28-10-4-16-46-22-28)36(60-42(54)30-12-6-18-48-24-30)35(59-41(53)29-11-5-17-47-23-29)33(31)57-39(51)27-9-3-15-45-21-27/h1-24,31-36H

[2,3,4,5,6-pentakis(pyridine-3-carbonyloxy)cyclohexyl] pyridine-3-carboxylate

NSC-49506; NSC 49506; Inositol niacinate

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)

DMSO :< 1 mg/mL

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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