Tocofersolan targets vitamin E deficiency and acts as an antioxidant. It also targets P-glycoprotein (P-gp), inhibiting its substrate-induced ATPase activity in cell-free assays with IC50 values of 0.4-3.25 µM. By inhibiting P-gp, it can enhance the oral bioavailability of other drugs that are substrates of this efflux transporter.

In vitro, Tocofersolan demonstrates antioxidant activity. It is also characterized by its surfactant properties and its ability to inhibit P-gp. Its critical micelle concentration (CMC) is 0.02 mM at room temperature. It is used to study the role of vitamin E in various biological processes and to enhance drug absorption.

In zebrafish embryos exposed to BaP at a concentration of 1 μM, tocofersolan (0-3 μM) significantly attenuates BaP-induced hypoactivity and enhances locomotor activity [3].
In vivo, Tocofersolan is used to treat vitamin E deficiency due to malabsorption in children with congenital or hereditary chronic cholestasis. It is approved by the European Medicines Agency (EMA) under the brand name Vedrop. It can reduce neurobehavioral deficits in zebrafish embryos exposed to BaP during early development.

The in vitro P-gp inhibition assay for Tocofersolan involves incubating the compound with P-gp membranes and a substrate, such as [3H]-taxol or a fluorescent dye. The accumulation of the substrate in the presence of the compound is measured, and the IC50 is calculated. Its surfactant properties are measured by its ability to reduce surface tension.

In vitro cell culture studies for Tocofersolan utilize Caco-2 cells, which express P-gp, to study its effect on drug permeability. Cells are treated with the compound, and the transport of a model P-gp substrate (e.g., rhodamine 123) is measured. Its antioxidant activity is assessed by measuring its ability to reduce ROS levels in cells.

In vivo animal experiments for Tocofersolan have been performed in zebrafish embryos to study its neuroprotective effects. In these studies, embryos are exposed to BaP, and the compound's ability to prevent neurobehavioral deficits is assessed. Its efficacy in treating vitamin E deficiency can be studied in animal models of cholestasis.

Absorption, Distribution and Excretion
Compared to other drugs, the bioavailability of vitamin E in tocofersolan sodium is unique. Due to its amphiphilic nature, it can form its own micelles, allowing for rapid absorption by intestinal cells even in the absence of bile salts; upon hydrolysis, it releases the lipid-soluble d-α-tocopherol. This formulation significantly improves the absorption rate of d-α-tocopherol compared to direct administration of free d-α-tocopherol. Furthermore, tocofersolan sodium may enhance the absorption of water-insoluble substances and other lipid-soluble vitamins. Tocofersolan sodium is a prodrug; its active metabolite is d-α-tocopherol. At low concentrations, tocofersolan sodium forms micelles, thereby enhancing the absorption of nonpolar lipids such as other lipid-soluble vitamins. The required micelle concentration is low (0.04 to 0.06 mmol/L). A pharmacokinetic study in 12 healthy subjects compared the pharmacokinetics of sodium tocopherol sulfate and water-soluble reference vitamin E after a single oral loading dose of 1200 IU (International Units). Results showed that the relative bioavailability of sodium tocopherol sulfate was 1.01 ± 1.74 (Frel), AUC0-t was 0.383 ± 0.203 μM·h/mg, Cmax was 0.013 ± 0.006 μM·h/mg, and Tmax was 6.0 h (6.0–24.0 h). For more information on vitamin E metabolism, see the drug entry [DB11251]. Vitamin E is primarily excreted via bile (75%) and feces, existing as free tocopherol or in oxidized form. Urine is a secondary route of excretion for vitamin E (in glucuronide conjugate form). Vitamin E is primarily found in cell membranes, mitochondria, and microsomes, and is widely distributed throughout the body (red blood cells, brain, muscles, liver, platelets), with adipose tissue being its main storage depot. Metabolism/Metabolites: Tocopherol is hydrolyzed in the intestinal lumen. Tocopherol is absorbed by cells, with its α-tocopherol fraction appearing in chylomicrons of the lymphatic system in the same manner as dietary vitamin E. Cellular uptake does not require receptors, binding proteins, or metabolic processes, nor is it carried out via endocytosis. The absorption of deuterated tocopherol follows a normal pattern in lipoproteins: α-tocopherol first peaks in chylomicrons, then in very low-density lipoprotein (VLDL), and finally in low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Biological half-life: 29.7 hours.
Tocofersolan has a molecular formula of C35H58O6 and a molecular weight of 574.83 g/mol. It is a solid compound that is soluble in water and organic solvents. It is typically stored as a powder at -20°C for long-term stability. Its stability is maintained under recommended storage conditions. It is a nonionic surfactant.

Protein Binding
It is highly bound to lipoproteins.
Toxicological data for Tocofersolan indicate that it is generally safe and well-tolerated. It is approved for use in pediatric patients with chronic cholestasis. It has a low potential for toxicity. However, as a surfactant, it may cause gastrointestinal irritation at high doses. It is not intended for use in adults with normal vitamin E status.

[1]. Antioxidant capacity in Fasciola hepatica patients before and after treatment with triclabendazole alone or in combination with ascorbic acid (vitamin C) and tocofersolan (vitamin E). Arzneimittelforschung. 2003;53(3):214-20.

[2]. Recent developments in d-α-tocopheryl polyethylene glycol-succinate-based nanomedicine for cancer therapy [published correction appears in Drug Deliv. 2017 Nov;24(1):1930]. Drug Deliv. 2017;24(1):1831-1842.

[3]. The use of tocofersolan as a rescue agent in larval zebrafish exposed to benzo[a]pyrene in early development. Neurotoxicology. 2021 Sep;86:78-84.

D-α-Tocopherol polyethylene glycol 1000 succinate (Tocofersolan, Vedrop) has been developed in Europe as a highly bioavailable oral source of vitamin E for the treatment of cholestasis in children. Cholestasis is characterized by reduced or absent bile flow, which may be caused by impaired or blocked secretion by hepatocytes. Tocofersolan is a polyethylene glycol derivative of α-tocopherol and is the synthetic water-soluble version of [DB11251]. Tocofersolan is used to treat vitamin E deficiency due to malabsorption in children with congenital or hereditary chronic cholestasis. The product was approved by the European Medicines Agency (EMA) in June 2009 under the brand name Vedrop. In addition, the drug has antioxidant properties and is therefore a common ingredient in cosmetics and pharmaceuticals. Besides the above uses, sodium tocopherol sulfate (tocofersolan) has been investigated as a promising drug delivery and absorption enhancer [MSDS].
See also: Vitamin E polyethylene glycol succinate (note moved to). Drug Indications Tocofersolan sodium is indicated for vitamin E deficiency caused by malabsorption, and is suitable for children with congenital or hereditary chronic cholestasis from birth (full-term newborns) to 18 years of age. FDA Label Mechanism of Action Vitamin E is a major fat-soluble antioxidant in the human body. As a free radical chain-terminating molecule, it can prevent the peroxidation of polyunsaturated fatty acids and plays an important role in maintaining the stability and integrity of cell membranes. Pharmacodynamics Due to its high solubility, this drug can easily penetrate cells, unlike other strictly fat-soluble vitamin E [MSDS]. For cholestasis, tocofersolan sodium promotes vitamin E absorption, thereby restoring vitamin E levels to normal and alleviating the symptoms of vitamin E deficiency.
Tocofersolan (Vedrop) is an approved drug in the European Union for the treatment of vitamin E deficiency in pediatric patients with congenital or hereditary chronic cholestasis. It is available as an oral solution. It is not approved in the United States. It is also used as a pharmaceutical excipient (TPGS) to enhance the solubility and bioavailability of other drugs.

C35H58O6

574.84

574.423

9002-96-4

59-02-9 (vitamin E);58-95-7 (acetate);17407-37-3 (Hemisuccinate);9002-96-4 (PEG 1000 succinate);

9938056

Off-white to light yellow <34°C powder,>38°C liquid

1.01g/cm3

662.7ºC at 760mmHg

34-38ºC

195.4ºC

1.496

8.388

1

6

20

41

768

3

C(=O)(OC1C(C)=C2CCC(C)(CCCC(CCCC(CCCC(C)C)C)C)OC2=C(C)C=1C)CCC(=O)OCO

AOBORMOPSGHCAX-AZAGJHQNSA-N

InChI=1S/C35H58O6/c1-24(2)12-9-13-25(3)14-10-15-26(4)16-11-20-35(8)21-19-30-29(7)33(27(5)28(6)34(30)41-35)40-32(38)18-17-31(37)39-23-22-36/h24-26,36H,9-23H2,1-8H3/t25-,26-,35-/m1/s1

D –α-TocopherolPEG 1000 succinate 2-hydroxyethyl (2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-yl) succinate

Vitamin E-TPGSD –α-Tocopherol PEG 1000 succinate TPGS,D-α-Tocopherol polyethylene glycol succinate, Vitamin E polyethylene glycol succinate,

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 (~66.09 mM)
H2O : ~100 mg/mL (~66.09 mM)
Ethanol : ~50 mg/mL (~33.05 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (1.65 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 (1.65 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 (1.65 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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Solubility in Formulation 4: ≥ 2.5 mg/mL (1.65 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
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 5: ≥ 2.5 mg/mL (1.65 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
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 6: 100 mg/mL (66.09 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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