DL-alpha-tocopheryl acetate is a model vitamin E extensively used in enteral nutrition formulations [1]. Myeloma, the heart, and liver cancer all have elevated tissue cholesterol levels due to DL-alpha-tocopheryl acetate (alpha-TA). The brain turns away from other tissues in a horizontal direction when protein levels are changed. Mice liver, brain, and heart muscle pellets treated with DL-α-tocopherol acetate also exhibit elevated levels of mitochondrial peroxidation [2].

Absorption, Distribution and Excretion
_In addition to any following information, owing to d-alpha-Tocopherol acetate's closely related chemical nature with alpha-Tocopherol acetate, please also refer to the drug information page for alpha-Tocopherol acetate for further data._ 50 to 80% absorbed from gastrointestinal tract.
_In addition to any following information, owing to d-alpha-Tocopherol acetate's closely related chemical nature with alpha-Tocopherol acetate, please also refer to the drug information page for alpha-Tocopherol acetate for further data._
_In addition to any following information, owing to d-alpha-Tocopherol acetate's closely related chemical nature with alpha-Tocopherol acetate, please also refer to the drug information page for alpha-Tocopherol acetate for further data._
_In addition to any following information, owing to d-alpha-Tocopherol acetate's closely related chemical nature with alpha-Tocopherol acetate, please also refer to the drug information page for alpha-Tocopherol acetate for further data._
When vitamin E is ingested, intestinal absorption plays a principal role in limiting its bioavailability. It is known that vitamin E is a fat-soluble vitamin that follows the intestinal absorption, hepatic metabolism, and cellular uptake processes of other lipophilic molecules and lipids. The intestinal absorption of vitamin E consequently requires the presence of lipid-rich foods. In particular, stable alpha-tocopherol acetate undergoes hydrolysis by bile acid-dependant lipase in the pancreas or by an intestinal mucosal esterase. Subsequent absorption in the duodenum occurs by way of transfer from emulsion fat globules to water-soluble multi- and unilamellar vesicles and mixed micelles made up of phospholipids and bile acids. As the uptake of vitamin E into enterocytes is less efficient compared to other types of lipids, this could potentially explain the relatively low bioavailability of vitamin E. Alpha-tocopherol acetate itself is embedded in matrices where its hydrolysis and its uptake by intestinal cells are markedly less efficient than in mixed micelles. Subsequently, the intestinal cellular uptake of vitamin E from mixed micelles follows in principle two different pathways across enterocytes: (a) via passive diffusion, and (b) via receptor-mediated transport with various cellular transports like scavenger receptor class B type 1, Niemann-Pick C1-like protein, ATP-binding cassette (ABC) transporters ABCG5/ABCG8, or ABCA1, among others. Vitamin E absorption from the intestinal lumen is dependent upon biliary and pancreatic secretions, micelle formation, uptake into enterocytes, and chylomicron secretion. Defects at any step can lead to impaired absorption.. Chylomicron secretion is required for vitamin E absorption and is a particularly important factor for efficient absorption. All of the various vitamin E forms show similar apparent efficiencies of intestinal absorption and subsequent secretion in chylomicrons. During chylomicron catabolism, some vitamin E is distributed to all the circulating lipoproteins. Chylomicron remnants, containing newly absorbed vitamin E, are then taken up by the liver. Vitamin E is secreted from the liver in very low density lipoproteins (VLDLs). Plasma vitamin E concentrations depend upon the secretion of vitamin E from the liver, and only one form of vitamin E, alpha-tocopherol, is ever preferentially resecreted by the liver. The liver is consequently responsible for discriminating between tocopherols and the preferential plasma enrichment with alpha-tocopherol. In the liver, the alpha-tocopherol transfer protein (alpha-TTP) likely is in charge of the discriminatory function, where RRR- or d-alpha-tocopherol possesses the greatest affinity for alpha-TTP. It is nevertheless believed that only a small amount of administered vitamin E is actually absorbed. In two individuals with gastric carcinoma and lymphatic leukemia, the respective fractional absorption in the lymphatics was only 21 and 29 percent of label from meals containing alpha-tocopherol and alpha-tocopheryl acetate, respectively. Additionally, after feeding three separate single doses of 125 mg, 250 mg, and 500 mg to a group of healthy males, the observed plasma peak concentrations (ng/mL) were 1822 +/- 48.24, 1931.00 +/- 92.54, and 2188 +/- 147.61, respectively.
The major route of excretion of ingested vitamin E is fecal elimination because of its relatively low intestinal absorption. Excess alpha-tocopherol, as well as forms of vitamin E not preferentially used, are probably excreted unchanged in bile.
When three particular doses alpha-tocopherol were administered to healthy male subjects, the apparent volumes of distribution (ml) observed were: (a) at a single administered dose of 125 mg, the Vd/f was 0.070 +/- 0.002, (b) at dose 250. mg, the Vd/f was 0.127 +/- 0.004, and (c) at dose 500 mg, the Vd/f was 0.232 +/- 0.010.
When three specific doses of 125 mg, 250 mg, and 500 mg of alpha-tocopherol were administered as single doses to a group of healthy males, the resultant times of clearance observed, respectively, were: 0.017 +/- 0.015 l/h, 0.011 +/- 0.001 l/h, and 0.019 +/- 0.001 l/h.

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Metabolism / Metabolites
_In addition to any following information, owing to d-alpha-Tocopherol acetate's closely related chemical nature with alpha-Tocopherol acetate, please also refer to the drug information page for alpha-Tocopherol acetate for further data._ Hepatic.
Primary hepatic metabolism of alpha-tocopherol begins in the endoplasmic reticulum with CYP4F2/CYP3A4 dependent ω-hydroxylation of the aliphatic side-chain, which forms the 13’-hydroxychromanol (13’-OH) metabolite. Next, peroxisome ω-oxidation results in 13’-carboxychromanol (13’-COOH). Following these two steps are five consecutive β-oxidation reactions which serve to shorten the alpha-tocopherol metabolite side-chains. The first of these β-oxidations occurs still in the peroxisome environment, generating carboxydimethyldecylhydroxychromanol (CDMDHC, 11’-COOH). Then, in the mitochondrion, the second β-oxidation step forms the carboxymethyloctylhydroxychromanol (CDMOHC, 9’-COOH) metabolite. Since both CDMDHC and CDMOHC possess a side-chain length of between 13 to 9 carbon units, they are considered long-chain metabolites. The hydrophobicity of these long-chain metabolites means they are not excreted in the urine but have been found in human microsomes, serum, and feces. The next two β-oxidation reactions, still within the mitochondrion environment, produce two intermediate chain metabolites: carboxymethylhexylhydroxychromanol (CDMHHC, 7’-COOH), followed by carboxymethylbutylhydroxychromanol (CMBHC, 5’-COOH). Both of these intermediate chain metabolites are found in human plasma, feces, and urine. Finally, the last mitochrondrion β-oxidation generates the catabolic end product of alpha-tocopherol metabolism: carboxyethyl-hydroxychromans (CEHC, 3'-COOH), which is considered a short-chain metabolite. CEHC has been observed in human plasma, serum, urine, and feces.

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Biological Half-Life
_In addition to any following information, owing to d-alpha-Tocopherol acetate's closely related chemical nature with alpha-Tocopherol acetate, please also refer to the drug information page for alpha-Tocopherol acetate for further data._
The apparent half-life of RRR- or d-alpha-tocopherol in normal subjects is approximately 48 hours.

Protein Binding
_In addition to any following information, owing to d-alpha-Tocopherol acetate's closely related chemical nature with alpha-Tocopherol acetate, please also refer to the drug information page for alpha-Tocopherol acetate for further data._ Bound to beta-lipoproteins in blood.
Data regarding the protein binding of alpha-tocopherol is not readily accessible at the moment. In fact, the existence of alpha-tocopherol binding proteins in tissues other than the liver is involved in ongoing investigations.

[1]. Double-balloon jejunal perfusion to compare absorption of vitamin E and vitamin E acetate in healthy volunteers under maldigestion conditions. Eur J Clin Nutr. 2013 Feb;67(2):202-6.

[2]. α-Tocopheryl phosphate: uptake, hydrolysis, and antioxidant action in cultured cells and mouse. Free Radic Biol Med. 2011 Jun 15;50(12):1794-800.

Pharmacodynamics
_In addition to any following information, owing to d-alpha-Tocopherol acetate's closely related chemical nature with alpha-Tocopherol acetate, please also refer to the drug information page for alpha-Tocopherol acetate for further data._ Vitamin E has antioxidant activity. It may also have anti-atherogenic, antithrombotic, anticoagulant, neuroprotective, antiviral, immunomodulatory, cell membrane-stabilizing and antiproliferative actions. Vitamin E is a collective term used to describe eight separate forms, the best-known form being alpha-tocopherol. Vitamin E is a fat-soluble vitamin and is an important antioxidant. It acts to protect cells against the effects of free radicals, which are potentially damaging by-products of the body's metabolism. Vitamin E is often used in skin creams and lotions because it is believed to play a role in encouraging skin healing and reducing scarring after injuries such as burns. There are three specific situations when a vitamin E deficiency is likely to occur. It is seen in persons who cannot absorb dietary fat, has been found in premature, very low birth weight infants (birth weights less than 1500 grams, or 3½ pounds), and is seen in individuals with rare disorders of fat metabolism. A vitamin E deficiency is usually characterized by neurological problems due to poor nerve conduction. Symptoms may include infertility, neuromuscular impairment, menstrual problems, miscarriage and uterine degradation. Preliminary research has led to a widely held belief that vitamin E may help prevent or delay coronary heart disease. Antioxidants such as vitamin E help protect against the damaging effects of free radicals, which may contribute to the development of chronic diseases such as cancer. It also protects other fat-soluble vitamins (A and B group vitamins) from destruction by oxygen. Low levels of vitamin E have been linked to increased incidence of breast and colon cancer.
Of the eight separate variants of vitamin E, alpha-tocopherol is the predominant form of vitamin E in human and animal tissues, and it has the highest bioavailability. This is because the liver preferentially resecretes only alpha-tocopherol by way of the hepatic alpha-tocopherol transfer protein (alpha-TTP); the liver metabolizes and excretes all the other vitamin E variants, which is why blood and cellular concentrations of other forms of vitamin E other than alpha-tocopherol are ultimately lower. Furthermore, the term alpha-tocopherol generally refers to a group of eight possible stereoisomers which is often called all-rac-tocopherol for being a racemic mixture of all eight stereoisomers. Of the eight stereoisomers, the RRR-alpha-tocopherol - or sometimes referred to as the d-alpha-tocopherol - stereoisomer is the naturally occurring form of alpha-tocopherol that is perhaps best recognized by the alpha-TTP and has been reported to demonstrate approximately twice the systemic availability of all-rac-tocopherol. As a result, often times (but certainly not always) the discussion of vitamin E - at least within the context of using the vitamin for health-related indications - is generally in reference to the use of RRR- or d-alpha-tocopherol.

C31H52O3

472.74278

472.391

52225-20-4

86472

Colorless to light yellow oil

0.9±0.1 g/cm3

485.3±0.0 °C at 760 mmHg

82 °F (NTP, 1992)

235.6±24.7 °C

0.0±1.2 mmHg at 25°C

1.488

12.07

0

3

14

34

602

3

CC(CCC[C@H](CCC[C@H](CCC[C@@]1(CCC2=C(C(OC(C)=O)=C(C(C)=C2O1)C)C)C)C)C)C.CC(CCC[C@H](C)CCC[C@H](C)CCC[C@@]3(C)CCC4=C(C(OC(C)=O)=C(C(C)=C4O3)C)C)C

ZAKOWWREFLAJOT-CEFNRUSXSA-N

InChI=1S/C31H52O3/c1-21(2)13-10-14-22(3)15-11-16-23(4)17-12-19-31(9)20-18-28-26(7)29(33-27(8)32)24(5)25(6)30(28)34-31/h21-23H,10-20H2,1-9H3/t22-,23-,31-/m1/s1

[(2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-3,4-dihydrochromen-6-yl] acetate

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 : ≥ 100 mg/mL (~211.53 mM)
H2O : ~100 mg/mL (~211.53 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.29 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 (5.29 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 (5.29 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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 (Please use freshly prepared in vivo formulations for optimal results.)