Tocofersolan

Identification

Summary

Tocofersolan is a derivative of alpha tocopherol used to treat vitamin E deficiencies.

Brand Names

Vedrop

Generic Name

Tocofersolan

DrugBank Accession Number

DB11635

Background

D-Alpha-tocopheryl polyethylene glycol 1000 succinate (Tocofersolan, Vedrop), has been developed in Europe as an orally bioavailable source of vitamin E in children suffering from cholestasis ³. Cholestasis is the reduction or stoppage of bile flow, either to impaired secretion by hepatocytes (liver cells) or obstruction ⁴, ⁵.

Tocofersolan is a polyethylene glycol derivative of α-tocopherol and synthetic water-soluble version of Tocopherol. Tocofersolan is an oral treatment of vitamin E deficiency due to digestive malabsorption in pediatric patients with congenital chronic cholestasis or hereditary chronic cholestasis. It was approved by the European Medicines Agency (EMA) in June 2009 under the market name Vedrop. Moreover, the agent is capable of demonstrating antioxidant effects that make it a popular component to include in cosmetics and pharmaceuticals as well.

In addition to the above, tocofersolan has been studied as a promising application as an absorption enhancer in drug delivery ^MSDS.

Type

Small Molecule

Groups

Approved

Synonyms

• (+)-.ALPHA.-TOCOPHERYL POLYETHYLENE GLYCOL 1000 SUCCINATE
• D-.ALPHA.-TOCOPHEROL POLYETHYLENE GLYCOL 1000 SUCCINATE
• Mono-[2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-6-chromanyl] succinate polyethylene glycol monoester
• POLY(OXY-1,2-ETHANEDIYL), .ALPHA.-(4-((3,4-DIHYDRO-2,5,7,8-TETRAMETHYL-2-(4,8,12-TRIMETHYLTRIDECYL)-2H-1-BENZOPYRAN-6-YL)OXY)-1,4-DIOXOBUTYL-.OMEGA.-HYDROXY-
• Tocofersolan
• Tocofersolano
• Tocofersolanum
• Tocophersolan
• TPG-S
• TPGS
• VITAMIN E POLYETHYLENE GLYCOL 1000 SUCCINATE
• VITAMIN E POLYETHYLENE GLYCOL SUCCINATE

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Pharmacology

Indication

Tocofersolan is indicated in vitamin E deficiency caused by digestive malabsorption in pediatric patients with congenital chronic cholestasis or hereditary chronic cholestasis from birth (full term newborns) up to 18 years of age ³.

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Vitamin e deficiency		••••••••••••			••••••••

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Pharmacodynamics

Because of its increased solubility ⁴, ⁶, ⁹, this medication readily penetrates cells, unlike other types of vitamin E ^MSDS, which are strictly fat-soluble ^MSDS. Specific to cholestasis, tocofersolan normalizes vitamin E levels relieving the symptoms of deficiency because of its facilitation of vitamin E absorption ³, ⁸.

Mechanism of action

Vitamin E is a major lipo-soluble antioxidant in humans. It acts as a free radical chain breaking molecule, halting the peroxidation of polyunsaturated fatty acids and it plays an important role in maintaining both the stability and integrity of cell membranes ³.

Target	Actions	Organism
UP-glycoprotein 1	antagonist	Humans

Absorption

The bioavailability of vitamin E from tocofersolan is unique from than that of other medicinal products ³.

Due to its amphipathic property in which it forms its own micelles, tocofersolan is readily taken up into enterocytes, even in the absence of bile salts; fat-soluble d-alpha-tocopherol is then released after hydrolysis. This formulation enhances the absorption of d-alpha-tocopherol compared to the administration of free d-alpha-tocopherol. Additionally, tocophersolan may enhance the absorption of water-insoluble agents and other fat-soluble vitamins ⁶.

Tocofersolan is a pro-drug; the active metabolite is the d-alpha-tocopherol. At low concentrations, tocofersolan forms micelles which improve the absorption of non-polar lipids such as other fat-soluble vitamins. Its required micellar concentration is low (0.04 to 0.06 mmol/l) ³.

A pharmacokinetic study of 12 healthy subjects compared tocofersolan with a water-miscible reference vitamin E after one single oral loading dose of 1200 IU (international units). The relative bioavailability of tocofersolan was found to be (Frel of 1.01 ± 1.74) with AUC0-t of 0.383 ± 0.203μM.h/mg, Cmax of 0.013 ± 0.006, Tmax of 6.0 h (6.0 – 24.0) ³.

For more information about Vitamin E metabolism, please visit the drug entry Tocopherol.

Volume of distribution

Located principally on cell membranes, within mitochondria and microsomes, vitamin E is widely distributed throughout the body (red blood cells, brain, muscle, liver, platelets) and fat tissues are its primary reservoir ³.

Protein binding

Highly bound to lipoproteins ³.

Metabolism

The hydrolysis of tocofersolan occurs in the gut lumen. Tocofersolan is absorbed by cells, and the alpha-tocopherol moiety appears in chylomicrons in the lymph system in a manner that is identical to vitamin E absorbed from dietary sources. Cellular uptake does not require receptors, binding proteins or metabolic processes and does not occur by pinocytosis. Absorption of deuterated tocofersolan demonstrated a normal pattern in lipoproteins: alpha-tocopherol peaked first in chylomicrons, then peaked in very low- density lipoproteins (VLDL) and finally in low-density lipoproteins (LDL) and high-density lipoproteins (HDL)³.

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• Tocofersolan
  • Vitamin E

Route of elimination

Vitamin E is primarily eliminated in the bile (75%) and feces, either as free tocopherol or in oxidized forms. Urine is a minor elimination route of vitamin E (as glucuronic-conjugate) ³.

Half-life

29.7 h ³

Clearance

Not Available

Adverse Effects

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Toxicity

> 7 g/kg ( Rat ) ¹⁰

Common adverse reactions

The most commonly reported adverse reaction during treatment is diarrhea ³. High doses of Vitamin E may cause diarrhea, abdominal pain, and other gastrointestinal conditions. In the case of an overdose, symptomatic treatment should be provided ³. High doses of vitamin E have been reported to increase bleeding tendency in patients with Vitamin K deficiency, or patients taking oral anti-vitamins K treatment ³. Therefore, careful monitoring of the prothrombin time and international normalized ratio (INR) are advised. A possible adjustment of the dose of oral anticoagulant during and after treatment with Vedrop may be necessary ³.

Renal impairment

Data regarding patients with renal impairment are limited, this drug should be administered with caution and those with renal impairment or dehydration should be closely followed ³.

Hepatic impairment

This drug should be administered with caution in patients with liver impairment and under close monitoring of the liver function tests in such patients ³.

Hypersensitivity

Vedrop, the commercial form, contains sodium methyl parahydroxybenzoate (E219) and sodium ethyl parahydroxybenzoate (E215) which may cause allergic reactions, which are sometimes delayed ³.

Pregnancy

There is no current data on taking tocofersolan during pregnancy. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/ fetal development, parturition or postnatal development. Caution should be taken when prescribing this medication to pregnant women ³.

Breast-feeding

It is unknown whether tocofersolan is released into human breast milk. The excretion of tocofersolan in milk has not been studied in animals ³.

Fertility

No data is available ³.

Pathways

Not Available

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Not Available

Interactions

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This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abametapir	The serum concentration of Tocofersolan can be increased when it is combined with Abametapir.
Amiodarone	The metabolism of Tocofersolan can be decreased when combined with Amiodarone.
Amprenavir	The metabolism of Tocofersolan can be decreased when combined with Amprenavir.
Apalutamide	The serum concentration of Tocofersolan can be decreased when it is combined with Apalutamide.
Aprepitant	The metabolism of Tocofersolan can be decreased when combined with Aprepitant.

Food Interactions

No interactions found.

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Vedrop	Solution	50 mg/mL	Oral	Recordati Rare Diseases	2017-09-15	Not applicable
Vedrop	Solution	50 mg/mL	Oral	Recordati Rare Diseases	2017-09-15	Not applicable
Vedrop	Solution	50 mg/mL	Oral	Recordati Rare Diseases	2017-09-15	Not applicable

Over the Counter Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Aquasol E Tpgs Liquid 77iu/ml	Liquid	77 unit / mL	Oral	Columbia Laboratories	1996-10-21	2009-07-17

Unapproved/Other Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
NESTABS ABC Prenatal Multi-vitamin/Mineral Supplement with DHA/EPA	Tocofersolan (30 [iU]/1) + Ascorbic acid (120 mg/1) + Calcium (155 mg/1) + Calcium carbonate (45 mg/1) + Cholecalciferol (450 [iU]/1) + Choline bitartrate (55 mg/1) + Cyanocobalamin (10 ug/1) + Doconexent (120 mg/1) + Folic acid (1 mg/1) + Icosapent (180 mg/1) + Iron (32 mg/1) + Niacin (20 mg/1) + Potassium Iodide (100 ug/1) + Pyridoxine hydrochloride (50 mg/1) + Riboflavin (3 mg/1) + Thiamine chloride (3 mg/1) + Tocopherol (10 mg/1) + Zinc (10 mg/1)	Capsule, gelatin coated; Kit; Tablet	Oral	WOMENS CHOICE PHARMACEUTICALS LLC	2011-02-01	2018-03-01
Pre-Tabs DHA Prenatal Multi-vitamin/Mineral Supplement with DHA/EPA	Tocofersolan (30 [iU]/1) + Calcium carbonate (45 mg/1) + Cholecalciferol (450 [iU]/1) + Choline bitartrate (55 mg/1) + Cyanocobalamin (10 ug/1) + Doconexent (230 mg/1) + Ferrous bisglycinate (32 mg/1) + Folic acid (1 mg/1) + Calcium formate (155 mg/1) + Icosapent (30 mg/1) + Nicotinamide (20 mg/1) + Potassium Iodide (100 ug/1) + Pyridoxine hydrochloride (50 mg/1) + Riboflavin (3 mg/1) + Sodium ascorbate (120 mg/1) + Thiamine mononitrate (3 mg/1) + Vitamin E (2 [iU]/1) + Zinc oxide (10 mg/1)	Kit	Oral	DEREMETRX LLC	2014-06-15	Not applicable

Categories

ATC Codes

A11HA08 — Tocofersolan

• A11HA — Other plain vitamin preparations
• A11H — OTHER PLAIN VITAMIN PREPARATIONS
• A11 — VITAMINS
• A — ALIMENTARY TRACT AND METABOLISM

Drug Categories

• Alimentary Tract and Metabolism
• Benzopyrans
• Compounds used in a research, industrial, or household setting
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Substrates
• Drug Carriers
• Heterocyclic Compounds, Fused-Ring
• Pyrans
• Vitamin E
• Vitamins
• Vitamins (Fat Soluble)

Classification

Not classified

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

O03S90U1F2

CAS number

9002-96-4

References

General References

1. Thebaut A, Nemeth A, Le Mouhaer J, Scheenstra R, Baumann U, Koot B, Gottrand F, Houwen R, Monard L, de Micheaux SL, Habes D, Jacquemin E: Oral Tocofersolan Corrects or Prevents Vitamin E Deficiency in Children With Chronic Cholestasis. J Pediatr Gastroenterol Nutr. 2016 Dec;63(6):610-615. doi: 10.1097/MPG.0000000000001331. [Article]
2. Roongpraiwan R, Suthutvoravut U, Feungpean B, Phuapradit P: Effect of oral vitamin E supplementation in children with cholestasis. J Med Assoc Thai. 2002 Nov;85 Suppl 4:S1199-205. [Article]
3. EMA Summary Assessment Report [Link]
4. Cholestasis [Link]
5. Emedicine, Cholestasis [Link]
6. Tocophersolan, PubChem [Link]
7. Parmentier document [Link]
8. Dosage and formulation issues: oral vitamin E therapy in children [Link]
9. Scottish Medicines Document, Tocofersolan [Link]
10. MSDS, Santa Cruz [Link]
11. Vitamin E Regulatory Mechanisms [Link]
12. α-TOCOPHEROL β-OXIDATION LOCALIZED TO RAT LIVER MITOCHONDRIA [Link]
13. EMA Summary of Product Characteristics: Vedrop (tocofersolan) oral solution [Link]

External Links

PubChem Substance

347911221

RxNav

159151

Wikipedia

Tocofersolan

FDA label

Download (345 KB)

MSDS

Download (160 KB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
3	Completed	Treatment	Hypobetalipoproteinemias	1
2	Withdrawn	Treatment	Short Bowel Syndrome (SBS) / Vitamin E Deficiency	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule	Oral	500.000 UI
Liquid	Oral	77 unit / mL
Capsule	Oral	400.000 mg
Solution	Parenteral
Capsule, gelatin coated; kit; tablet	Oral
Kit	Oral
Solution	Oral	50 MG/ML

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	34-38	MSDS
water solubility	soluble at 1g/10 mL	MSDS

Predicted Properties

Not Available

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Not Available

Chromatographic Properties

Collision Cross Sections (CCS)

Not Available

Targets

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Details1. P-glycoprotein 1

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Antagonist

General Function

Xenobiotic-transporting atpase activity

Specific Function

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.

Gene Name

ABCB1

Uniprot ID

P08183

Uniprot Name

Multidrug resistance protein 1

Molecular Weight

141477.255 Da

References

1. EMA Summary Assessment Report [Link]

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Drug created at October 17, 2016 21:27 / Updated at September 28, 2023 05:40