Identification

Name
Tocofersolan
Accession Number
DB11635
Type
Small Molecule
Groups
Approved
Description

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. Tocofersolan is also used in cosmetics and pharmaceuticals as an antioxidant.

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

Synonyms
  • Tocofersolano
  • Tocofersolanum
  • Tocophersolan
  • TPG-S
  • TPGS
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
VedropSolution50 mg/mLOralOrphan Europe S.A.R.L.2009-07-24Not applicableEu
VedropSolution50 mg/mLOralOrphan Europe S.A.R.L.2009-07-24Not applicableEu
VedropSolution50 mg/mLOralOrphan Europe S.A.R.L.2009-07-24Not applicableEu
Over the Counter Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Aquasol E Tpgs Liquid 77iu/mlLiquid77 unitOralColumbia Laboratories1996-10-212009-07-17Canada
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
NESTABS ABC Prenatal Multi-vitamin/Mineral Supplement with DHA/EPATocofersolan (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) + Vitamin E (2 [iU]/1) + Zinc (10 mg/1)KitWomens Choice Pharmaceuticals, Llc2013-10-01Not applicableUs
Pre-Tabs DHA Prenatal Multi-vitamin/Mineral Supplement with DHA/EPATocofersolan (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)KitDEREMETRX LLC2014-06-15Not applicableUs
Categories
UNII
O03S90U1F2
CAS number
9002-96-4
Weight
Not Available
Chemical Formula
C33H54O5(C2H4O)n
InChI Key
Not Available
InChI
Not Available
IUPAC Name
Not Available
SMILES
Not Available

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].

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].

TargetActionsOrganism
UMultidrug resistance protein 1
antagonist
Human
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].

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
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].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Tocofersolan can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Tocofersolan.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Tocofersolan.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Tocofersolan.
5-androstenedioneThe metabolism of Tocofersolan can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Tocofersolan can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Tocofersolan.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Tocofersolan.
AbirateroneThe metabolism of Tocofersolan can be decreased when combined with Abiraterone.
AcalabrutinibThe metabolism of Tocofersolan can be decreased when combined with Acalabrutinib.
Food Interactions
Not Available

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. [PubMed:27429423]
  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. [PubMed:12549795]
  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]
External Links
PubChem Substance
347911221
Wikipedia
Tocofersolan
ATC Codes
A11HA08 — Tocofersolan
FDA label
Download (345 KB)
MSDS
Download (160 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2Not Yet RecruitingTreatmentShort Bowel Syndrome (SBS) / Vitamin E Deficiency1
3CompletedTreatmentHypobetalipoproteinemias1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
LiquidOral77 unit
Kit
SolutionOral50 mg/mL
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)34-38MSDS
water solubility soluble at 1g/10 mLMSDS
Predicted Properties
Not Available
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Targets

Kind
Protein
Organism
Human
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]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Not Available
Specific Function
Not Available
Gene Name
CYP4F2
Uniprot ID
P78329
Uniprot Name
Phylloquinone omega-hydroxylase CYP4F2
Molecular Weight
59852.825 Da
References
  1. α-TOCOPHEROL β-OXIDATION LOCALIZED TO RAT LIVER MITOCHONDRIA [Link]
  2. Vitamin E Regulatory Mechanisms [Link]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Schmolz L, Birringer M, Lorkowski S, Wallert M: Complexity of vitamin E metabolism. World J Biol Chem. 2016 Feb 26;7(1):14-43. doi: 10.4331/wjbc.v7.i1.14. [PubMed:26981194]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Vitamin e binding
Specific Function
Binds alpha-tocopherol, enhances its transfer between separate membranes, and stimulates its release from liver cells (PubMed:7887897). Binds both phosphatidylinol 3,4-bisphosphate and phosphatidyl...
Gene Name
TTPA
Uniprot ID
P49638
Uniprot Name
Alpha-tocopherol transfer protein
Molecular Weight
31749.305 Da
References
  1. Schmolz L, Birringer M, Lorkowski S, Wallert M: Complexity of vitamin E metabolism. World J Biol Chem. 2016 Feb 26;7(1):14-43. doi: 10.4331/wjbc.v7.i1.14. [PubMed:26981194]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Virus receptor activity
Specific Function
Receptor for different ligands such as phospholipids, cholesterol ester, lipoproteins, phosphatidylserine and apoptotic cells. Probable receptor for HDL, located in particular region of the plasma ...
Gene Name
SCARB1
Uniprot ID
Q8WTV0
Uniprot Name
Scavenger receptor class B member 1
Molecular Weight
60877.385 Da
References
  1. Schmolz L, Birringer M, Lorkowski S, Wallert M: Complexity of vitamin E metabolism. World J Biol Chem. 2016 Feb 26;7(1):14-43. doi: 10.4331/wjbc.v7.i1.14. [PubMed:26981194]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Rab gtpase binding
Specific Function
Plays a major role in cholesterol homeostasis. Is critical for the uptake of cholesterol across the plasma membrane of the intestinal enterocyte. Is the direct molecular target of ezetimibe, a drug...
Gene Name
NPC1L1
Uniprot ID
Q9UHC9
Uniprot Name
Niemann-Pick C1-like protein 1
Molecular Weight
148726.52 Da
References
  1. Schmolz L, Birringer M, Lorkowski S, Wallert M: Complexity of vitamin E metabolism. World J Biol Chem. 2016 Feb 26;7(1):14-43. doi: 10.4331/wjbc.v7.i1.14. [PubMed:26981194]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Protein heterodimerization activity
Specific Function
Transporter that appears to play an indispensable role in the selective transport of the dietary cholesterol in and out of the enterocytes and in the selective sterol excretion by the liver into bile.
Gene Name
ABCG5
Uniprot ID
Q9H222
Uniprot Name
ATP-binding cassette sub-family G member 5
Molecular Weight
72503.02 Da
References
  1. Schmolz L, Birringer M, Lorkowski S, Wallert M: Complexity of vitamin E metabolism. World J Biol Chem. 2016 Feb 26;7(1):14-43. doi: 10.4331/wjbc.v7.i1.14. [PubMed:26981194]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Sterol transporter activity
Specific Function
Transporter that appears to play an indispensable role in the selective transport of the dietary cholesterol in and out of the enterocytes and in the selective sterol excretion by the liver into bile.
Gene Name
ABCG8
Uniprot ID
Q9H221
Uniprot Name
ATP-binding cassette sub-family G member 8
Molecular Weight
75678.03 Da
References
  1. Schmolz L, Birringer M, Lorkowski S, Wallert M: Complexity of vitamin E metabolism. World J Biol Chem. 2016 Feb 26;7(1):14-43. doi: 10.4331/wjbc.v7.i1.14. [PubMed:26981194]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Syntaxin binding
Specific Function
cAMP-dependent and sulfonylurea-sensitive anion transporter. Key gatekeeper influencing intracellular cholesterol transport.
Gene Name
ABCA1
Uniprot ID
O95477
Uniprot Name
ATP-binding cassette sub-family A member 1
Molecular Weight
254299.89 Da
References
  1. Schmolz L, Birringer M, Lorkowski S, Wallert M: Complexity of vitamin E metabolism. World J Biol Chem. 2016 Feb 26;7(1):14-43. doi: 10.4331/wjbc.v7.i1.14. [PubMed:26981194]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Transporter activity
Specific Function
Probable hydrophobic ligand-binding protein; may play a role in the transport of hydrophobic ligands like tocopherol, squalene and phospholipids.
Gene Name
SEC14L4
Uniprot ID
Q9UDX3
Uniprot Name
SEC14-like protein 4
Molecular Weight
46643.385 Da
References
  1. Schmolz L, Birringer M, Lorkowski S, Wallert M: Complexity of vitamin E metabolism. World J Biol Chem. 2016 Feb 26;7(1):14-43. doi: 10.4331/wjbc.v7.i1.14. [PubMed:26981194]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Vitamin e binding
Specific Function
Carrier protein. Binds to some hydrophobic molecules and promotes their transfer between the different cellular sites. Binds with high affinity to alpha-tocopherol. Also binds with a weaker affinit...
Gene Name
SEC14L2
Uniprot ID
O76054
Uniprot Name
SEC14-like protein 2
Molecular Weight
46144.9 Da
References
  1. Schmolz L, Birringer M, Lorkowski S, Wallert M: Complexity of vitamin E metabolism. World J Biol Chem. 2016 Feb 26;7(1):14-43. doi: 10.4331/wjbc.v7.i1.14. [PubMed:26981194]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Transporter activity
Specific Function
Probable hydrophobic ligand-binding protein; may play a role in the transport of hydrophobic ligands like tocopherol, squalene and phospholipids.
Gene Name
SEC14L3
Uniprot ID
Q9UDX4
Uniprot Name
SEC14-like protein 3
Molecular Weight
46047.835 Da
References
  1. Schmolz L, Birringer M, Lorkowski S, Wallert M: Complexity of vitamin E metabolism. World J Biol Chem. 2016 Feb 26;7(1):14-43. doi: 10.4331/wjbc.v7.i1.14. [PubMed:26981194]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Very-low-density lipoprotein particle receptor activity
Specific Function
Macrophage receptor that binds to the apolipoprotein B48 (APOB) of dietary triglyceride (TG)-rich lipoproteins (TRL) or to a like domain of APOB in hypertriglyceridemic very low density lipoprotein...
Gene Name
APOBR
Uniprot ID
Q0VD83
Uniprot Name
Apolipoprotein B receptor
Molecular Weight
114873.425 Da
References
  1. Schmolz L, Birringer M, Lorkowski S, Wallert M: Complexity of vitamin E metabolism. World J Biol Chem. 2016 Feb 26;7(1):14-43. doi: 10.4331/wjbc.v7.i1.14. [PubMed:26981194]

Drug created on October 17, 2016 15:27 / Updated on November 02, 2018 07:13