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
Due to the very similar chemical properties of d-α-tocopherol acetate and α-tocopherol acetate, please refer to the α-tocopherol acetate drug information page for more data, in addition to the information below. 50% to 80% is absorbed via the gastrointestinal tract. The chemical properties of d-α-tocopherol acetate are closely related to those of α-tocopherol acetate; for more information, please refer to the α-tocopherol acetate drug information page.
After vitamin E ingestion, intestinal absorption is the main factor limiting its bioavailability. Vitamin E is known to be a fat-soluble vitamin, and its absorption process is similar to other lipophilic molecules and lipids, following intestinal absorption, hepatic metabolism, and cellular uptake. Therefore, intestinal absorption of vitamin E requires a lipid-rich diet. Specifically, stable α-tocopherol acetate is hydrolyzed by bile acid-dependent lipases in the pancreas or by esterases in the intestinal mucosa. Subsequently, in the duodenum, vitamin E is absorbed via transfer from emulsified fat globules to water-soluble multilayered and single-layered vesicles composed of phospholipids and bile acids, as well as mixed micelles. Compared to other types of lipids, vitamin E is absorbed less efficiently by intestinal cells, which may explain its relatively low bioavailability. α-Tocopherol acetate itself is embedded in the matrix, and its hydrolysis and absorption by intestinal cells are significantly less efficient than those of mixed micelles. Therefore, vitamin E absorption from mixed micelles by intestinal cells mainly follows two distinct pathways: (a) passive diffusion; and (b) receptor-mediated transport involving various cellular transport proteins, such as type B scavenger receptors, Niemann-Pick C1-like proteins, and ATP-binding cassette (ABC) transporters ABCG5/ABCG8 or ABCA1. Vitamin E absorption from the intestinal lumen depends on bile and pancreatic juice secretion, micelle formation, absorption by intestinal cells, and chylomicron secretion. Defects in any of these steps can lead to malabsorption. Chylomicron secretion is essential for vitamin E absorption and is a key factor for efficient absorption. Various forms of vitamin E are absorbed into the intestine and subsequently secreted into chylomicrons with similar efficiency. During chylomicron catabolism, some vitamin E is allocated to all circulating lipoproteins. The chylomicron residue containing newly absorbed vitamin E is then absorbed by the liver. Vitamin E is secreted from the liver in the form of very low-density lipoprotein (VLDL). Plasma vitamin E concentration depends on the vitamin E secreted by the liver, and only one form of vitamin E—α-tocopherol—is preferentially re-secreted by the liver. Therefore, the liver is responsible for distinguishing between various tocopherols and preferentially enriching α-tocopherol in the plasma. In the liver, α-tocopherol transfer protein (α-TTP) may be responsible for distinguishing different forms of vitamin E, with RRR- or d-α-tocopherol having the highest affinity for α-TTP. However, it is believed that the actual amount of vitamin E absorbed is very small. In two patients with gastric cancer and lymphocytic leukemia, respectively, the lymphatic system absorbed 21% and 29% of the labeled amounts of dietary intake containing α-tocopherol and α-tocopheryl acetate, respectively. Furthermore, in a group of healthy men, after single doses of vitamin E of 125 mg, 250 mg, and 500 mg, the observed peak plasma concentrations (ng/mL) were 1822 ± 48.24, 1931.00 ± 92.54, and 2188 ± 147.61, respectively.
Because vitamin E has a relatively low intestinal absorption rate, its primary excretion route is fecal. Excess α-tocopherol and other unused forms of vitamin E may be excreted unchanged via bile.
When healthy male subjects were administered three specific doses of α-tocopherol, the observed apparent volumes of distribution (Vd/f) were: (a) 0.070 ± 0.002 for a single 125 mg dose; (b) 0.127 ± 0.004 for a 250 mg dose; and (c) 0.232 ± 0.010 for a 500 mg dose.
When a group of healthy men were administered three specific doses of α-tocopherol—125 mg, 250 mg, and 500 mg—the observed clearance times 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 the information below, since the chemical properties of d-α-tocopherol acetate are closely related to those of α-tocopherol acetate, please also refer to the α-tocopherol acetate drug information page for more data. _Hepatic Metabolism.
The main hepatic metabolism of α-tocopherol begins in the endoplasmic reticulum, via CYP4F2/CYP3A4-dependent aliphatic side chain ω-hydroxylation to generate the 13'-hydroxychromanol (13'-OH) metabolite. Next, peroxisome ω-oxidation generates 13'-carboxychromanol (13'-COOH). Following these two steps are five consecutive β-oxidation reactions designed to shorten the side chains of the α-tocopherol metabolite. The first β-oxidation reaction still occurs in the peroxisome environment, producing carboxydimethyldecylhydroxychromanol (CDMDHC, 11'-COOH). Subsequently, in the mitochondria, the second β-oxidation reaction produces the metabolite carboxymethyloctylhydroxychromanol (CDMOHC, 9'-COOH). Because CDMDHC and CDMOHC have side chains of 13 to 9 carbon atoms, they are considered long-chain metabolites. The hydrophobicity of these long-chain metabolites means they are not excreted in urine, but have been found in human microsomes, serum, and feces. The next two β-oxidation steps still occur in the mitochondrial environment, producing two intermediate metabolites: carboxymethylhexylhydroxychromanol (CDMHHC, 7'-COOH) and carboxymethylbutylhydroxychromanol (CMBHC, 5'-COOH). Both of these intermediate metabolites are present in human plasma, feces, and urine. Finally, the mitochondrial β-oxidation reaction produces the catabolic end product of α-tocopherol metabolism: carboxyethylhydroxychromanol (CEHC, 3'-COOH), which is considered a short-chain metabolite. CEHC has been detected in human plasma, serum, urine, and feces.

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Biological Half-Life
_In addition to the information below, please also refer to the drug information page for α-tocopherol acetate for more data, as the chemical properties of d-α-tocopherol acetate are closely related to those of α-tocopherol acetate._
The apparent half-life of RRR- or d-α-tocopherol in normal subjects is approximately 48 hours.

Protein Binding
_In addition to the information below, due to the very similar chemical properties of d-α-tocopherol acetate and α-tocopherol acetate, please also refer to the α-tocopherol acetate drug information page for more data. _ Binds to β-lipoprotein in the blood.
Currently, there is no data on α-tocopherol protein binding. In fact, the existence of α-tocopherol-binding proteins in tissues other than the liver is still under investigation.

[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 the information below, please refer to the drug information page for α-tocopherol acetate for more data, as the chemical properties of d-α-tocopherol acetate are closely related to those of α-tocopherol acetate. Vitamin E has antioxidant activity. It may also have anti-atherosclerotic, antithrombotic, anticoagulant, neuroprotective, antiviral, immunomodulatory, cell membrane stabilizing, and antiproliferative effects. Vitamin E is a collective term used to describe eight different forms, the most well-known of which is α-tocopherol. Vitamin E is a fat-soluble vitamin and an important antioxidant. It protects cells from free radicals, byproducts of human metabolism that can cause damage. Vitamin E is commonly used in skin creams and lotions because it is believed to help promote skin healing and reduce scarring after injuries such as burns. Vitamin E deficiency primarily occurs in three situations: individuals who cannot absorb dietary fat; premature infants, very low birth weight infants (birth weight less than 1500 grams, or 3.5 pounds); and individuals with rare lipid metabolism disorders. Vitamin E deficiency often manifests as neurological problems due to poor nerve conduction, and symptoms may include infertility, neuromuscular dysfunction, menstrual disorders, miscarriage, and uterine degeneration. Preliminary studies suggest that vitamin E may help prevent or delay the onset of coronary heart disease. Antioxidants such as vitamin E help protect against damage from free radicals, which can contribute to chronic diseases such as cancer. Furthermore, vitamin E protects other fat-soluble vitamins (vitamin A and B vitamins) from oxygen degradation. Low vitamin E levels are associated with an increased incidence of breast and colon cancer. Of the eight different vitamin E variants, alpha-tocopherol is the most abundant form of vitamin E in human and animal tissues and has the highest bioavailability. This is because the liver preferentially re-secretes α-tocopherol via hepatic α-tocopherol transfer protein (α-TTP); the liver metabolizes and excretes all other vitamin E variants, which is why blood and cellular concentrations of vitamin E other than α-tocopherol are ultimately lower. Furthermore, the term α-tocopherol generally refers to a group of eight possible stereoisomers, and because it is a racemic mixture of all eight stereoisomers, it is often called racemic tocopherol. Of the eight stereoisomers, RRR-α-tocopherol (sometimes also called d-α-tocopherol) is the naturally occurring form of α-tocopherol, which α-TTP may most accurately identify, and its systemic bioavailability has been reported to be approximately twice that of racemic tocopherol. Therefore, when discussing vitamin E—at least in the context of its use for health-related indications—it usually (but not always) refers to the use of RRR- or d-α-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.)