Identification

Name
Tocopherol
Accession Number
DB11251
Type
Small Molecule
Groups
Approved, Investigational
Description

Tocopherol exists in four different forms designated as α, β, δ, and γ. They present strong antioxidant activities, and it is determined as the major form of vitamin E. Tocopherol, as a group, is composed of soluble phenolic compounds that consist of a chromanol ring and a 16-carbon phytyl chain. The classification of the tocopherol molecules is designated depending on the number and position of the methyl substituent in the chromanol ring. The different types of tocopherol can be presented trimethylated, dimethylated or methylated in the positions 5-, 7- and 8-. When the carbons at position 5- and 7- are not methylated, they can function as electrophilic centers that can trap reactive oxygen and nitrogen species. Tocopherols can be found in the diet as part of vegetable oil such as corn, soybean, sesame, and cottonseed.[1] It is currently under the list of substances generally recognized as safe (GRAS) in the FDA for the use of human consumption.[10]

Synonyms
  • Methyltocols
  • tocoferol
  • tocoferoles
  • tocophérol
  • Tocopherols
External IDs
E-306 / E-MIX 80
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Aloe Vera SprayerTocopherol (0.5 g/100g) + Aloe Vera Leaf (2 g/100g) + Glycerin (4 g/100g) + Propylene glycol (2 g/100g)LiquidTopicalNINGBO JIANGBEI OCEAN STAR TRADING CO.,LTD2015-02-20Not applicableUs
Soin Solaire Complete SPF30Tocopherol (1 mg/1mL) + Calcium ascorbate dihydrate (.17 mg/1mL) + Calcium threonate (.001 mg/1mL) + Panthenol (7.5 mg/1mL) + Titanium dioxide (70 mg/1mL) + alpha-Tocopherol acetate (5 mg/1mL)EmulsionTopicalElemis Limited2012-03-272012-12-31Us
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
bdr Laser Effect Peptide Complex Face MaskTocopherol (0.105 g/30g) + Hyaluronic acid (0.51 g/30g)PatchTopicalHanaim International Llc2016-11-22Not applicableUs
Calming SkinTocopherol (0.65 mL/130mL) + Glycerin (0.65 mL/130mL) + Panthenol (0.65 mL/130mL)LotionTopicalAtomy Co., Ltd.2011-07-18Not applicableUs
Calming SkinTocopherol (0.65 mL/130mL) + Glycerin (0.65 mL/130mL) + Panthenol (0.65 mL/130mL)LotionTopicalATOMY CO LTD2011-06-222011-06-22Us
CiclopiroxTocopherol (50 mg/1) + Ciclopirox (80 mg/1mL)KitAcella Pharmaceuticals, LLC2008-10-272015-05-31Us
Conju PrincessTocopherol (1.1 g/100g)SoapTopicalConju Inc2015-12-25Not applicableUs
Conju Princess Cleansing BalmTocopherol (0.0032 g/100g)CreamTopicalConju Inc2016-03-14Not applicableUs
Multivitamin Drops with FluorideTocopherol (5 [iU]/1mL) + Ascorbic acid (35 mg/1mL) + Cholecalciferol (400 [iU]/1mL) + Cyanocobalamin (2 ug/1mL) + Riboflavin 5'-phosphate sodium (0.6 mg/1mL) + Nicotinamide (8 mg/1mL) + Pyridoxine hydrochloride (0.4 mg/1mL) + Sodium fluoride (0.5 mg/1mL) + Thiamine hydrochloride (0.5 mg/1mL) + Vitamin A palmitate (1500 [iU]/1mL)LiquidOralSancilio & Company, Inc.2017-08-242017-09-11Us
Multivitamin Drops with FluorideTocopherol (5 [iU]/1mL) + Ascorbic acid (35 mg/1mL) + Cholecalciferol (400 [iU]/1mL) + Cyanocobalamin (2 ug/1mL) + Nicotinamide (8 mg/1mL) + Pyridoxine (0.4 mg/1mL) + Riboflavin (0.6 mg/1mL) + Sodium fluoride (0.25 mg/1mL) + Thiamine (0.5 mg/1mL) + Vitamin A (1500 [iU]/1mL)Solution / dropsOralSancilio & Company, Inc.2017-04-102017-04-14Us
Multivitamin Drops with FluorideTocopherol (5 [iU]/1mL) + Ascorbic acid (35 mg/1mL) + Cholecalciferol (400 [iU]/1mL) + Cyanocobalamin (2 ug/1mL) + Riboflavin 5'-phosphate sodium (0.6 mg/1mL) + Nicotinamide (8 mg/1mL) + Pyridoxine hydrochloride (0.4 mg/1mL) + Sodium fluoride (0.25 mg/1mL) + Thiamine hydrochloride (0.5 mg/1mL) + Vitamin A palmitate (1500 [iU]/1mL)LiquidOralSancilio & Company, Inc.2017-08-242017-09-11Us
Multivitamin Drops with FluorideTocopherol (5 [iU]/1mL) + Ascorbic acid (35 mg/1mL) + Cholecalciferol (400 [iU]/1mL) + Cyanocobalamin (2 ug/1mL) + Nicotinamide (8 mg/1mL) + Pyridoxine (0.4 mg/1mL) + Riboflavin (0.6 mg/1mL) + Sodium fluoride (0.5 mg/1mL) + Thiamine chloride (0.5 mg/1mL) + Vitamin A (1500 [iU]/1mL)Solution / dropsOralSancilio & Company, Inc.2017-04-102017-04-14Us
Categories
UNII
R0ZB2556P8
CAS number
1406-66-2
Weight
Not Available
Chemical Formula
Not Available
InChI Key
Not Available
InChI
Not Available
IUPAC Name
Not Available
SMILES
Not Available

Pharmacology

Indication

Tocopherol can be used as a dietary supplement for patients with a deficit of vitamin E; this is mainly prescribed in the alpha form.[3] Vitamin E deficiency is rare, and it is primarily found in premature babies of very low birth weight, patients with fat malabsorption or patients with abetalipoproteinemia.[11]

Tocopherol, due to its antioxidant properties, is studied for its use in prevention or treatment in different complex diseases such as cancer,[1] atherosclerosis, cardiovascular diseases,[2] and age-related macular degeneration.[4]

Pharmacodynamics

The antioxidant effects of tocopherol can be translated into different changes at the pharmacodynamic level. In vitro studies have shown that this antioxidant activity can produce modification in protein kinase C (PKC) which will later be translated into an inhibition of cell death. Some other derivate effects are the anti-inflammatory properties of tocopherol which can be related to the modulation of cytokines or prostaglandins, prostanoids and thromboxanes.[5]

Mechanism of action

Tocopherol acts as a radical scavenger. It mainly acts as an antioxidant for lipid bilayers. Tocopherol's functions depend on the H-atom donating ability, location, and movement within the membrane, as well as the efficiency in the radical recycling by some cytosolic reductants such as ascorbate.[5] Tocopherol actions are related to the trap of radicals, and it has been shown that even in the absence of substituents in the ortho-positions, tocopherol can trap more than two radicals. The type of radicals available for tocopherol are alkyl and peroxy.[12]

TargetActionsOrganism
AFree radicals
binder
Human
Absorption

The absorption of tocopherol in the digestive tract requires the presence of fat.[11] The approximate tmax of the four different isomers of tocopherol is attained in the range of 3-6 hours. When compared with tocotrienols, tocopherols showed a reduced bioavailability. The bioavailability of tocopherols is highly dependent on the type of isomer that is administered where the alpha-tocopherol can present a bioavailability of 36%. This isomer specificity also determines the intestinal permeability in which the gamma-tocopherol presents a very low permeability. After oral administration, the Cmax, AUC and mean residence time of tocopherols showed to be dependent on the isomer and ranged from 590-2915 ng/ml, 3740-10169 ng/ml and 4.85-5.74 h, respectively.[6]

Volume of distribution

The apparent volume of distribution of tocopherol is approximately 0.5 ml.[6]

Protein binding

There has not been described a specific plasma transport protein for tocopherol but it is thought that it is highly bound to lipoproteins such as VLDL, HDL and chylomicrons.[8]

Metabolism

Excess tocopherol is converted into their corresponding carboxyethylhydroxychroman (CEHC), based on the isomer of tocopherol.[7] More deeply, the metabolism of tocopherol begins with the hepatic metabolism which is led by a CYP4F2/CYP3A4-dependent ω-hydroxylation of the side chains which leads to the formation of 13'-carboxychromanol. The metabolic pathway is followed by five cycles of β-oxidation. The β-oxidation cycles function by shortening the side chains, the first cycle results in the formation of carboxydimethyldecylhydroxychromanol followed by carboxymethyloctylhydroxychromanol. These two metabolites are categorized as long-chain metabolites and they are not excreted in the urine. Some intermediate-chain metabolites that are products of two rounds of β-oxidation are carboxymethylhexylhydroxychromanol and carboxymethylbutylhydroxychromanol. These intermediate-chain metabolites can be found in human feces and urine. The catabolic end-product of tocopherols, as stated before, is CEHC which can be largely found in urine and feces.[8]

Two new metabolites have been detected in human and mice feces. These new metabolites are 12'-hydroxychromanol and 11'-hydroxychromanol. Because of their chemistry, it is thought that these metabolites can be the evidence for a ω-1 and ω-2 hydroxylation which leads to an impaired oxidation of 12'-OH followed side-chain truncation.[8]

Route of elimination

The pharmacokinetic profile of tocopherol indicates a longer time of excretion for tocopherols when compared to tocotrienols.[6] The different conjugated metabolites are excreted in the urine or feces depending on the length of their side-chain.[7] Due to their polarity, intermediate-chain metabolites and short-chain metabolites are excreted via urine as glucoside conjugates. A mixture of all the metabolites and precursors can be found in feces. The long-chain metabolites correspond to >60% of the total metabolites in feces. It is estimated that the fecal excretion accounts for even 80% of the administered dose.[8]

Half life

The elimination half-life of tocopherol is approximately 2.6 hours.[6]

Clearance

The clearance rate of tocopherol is approximately 0.15 l/h.[6]

Toxicity

Tocopherols are considered as non-toxic but if very high doses are administered, there are reports of hemorrhagic activity. Reproductive and developmental toxicity tests are negative. These negative results were also observed in the analysis of mutagenicity and carcinogenicity.[9]

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

Interactions

Drug Interactions
DrugInteraction
AcetaminophenAcetaminophen may decrease the excretion rate of Tocopherol which could result in a higher serum level.
Acetyl sulfisoxazoleThe metabolism of Tocopherol can be decreased when combined with Acetyl sulfisoxazole.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Tocopherol which could result in a higher serum level.
AlclometasoneThe metabolism of Alclometasone can be decreased when combined with Tocopherol.
AlprazolamAlprazolam may decrease the excretion rate of Tocopherol which could result in a higher serum level.
AmilorideAmiloride may increase the excretion rate of Tocopherol which could result in a lower serum level and potentially a reduction in efficacy.
AmiodaroneThe metabolism of Tocopherol can be decreased when combined with Amiodarone.
AmlodipineAmlodipine may decrease the excretion rate of Tocopherol which could result in a higher serum level.
AmoxicillinAmoxicillin may decrease the excretion rate of Tocopherol which could result in a higher serum level.
AmphetamineAmphetamine may decrease the excretion rate of Tocopherol which could result in a higher serum level.
Food Interactions
Not Available

References

General References
  1. Das Gupta S, Suh N: Tocopherols in cancer: An update. Mol Nutr Food Res. 2016 Jun;60(6):1354-63. doi: 10.1002/mnfr.201500847. Epub 2016 Feb 2. [PubMed:26751721]
  2. Mathur P, Ding Z, Saldeen T, Mehta JL: Tocopherols in the Prevention and Treatment of Atherosclerosis and Related Cardiovascular Disease. Clin Cardiol. 2015 Sep;38(9):570-6. doi: 10.1002/clc.22422. Epub 2015 Aug 14. [PubMed:26272221]
  3. Kim HJ, Giovannucci E, Rosner B, Willett WC, Cho E: Longitudinal and secular trends in dietary supplement use: Nurses' Health Study and Health Professionals Follow-Up Study, 1986-2006. J Acad Nutr Diet. 2014 Mar;114(3):436-43. doi: 10.1016/j.jand.2013.07.039. Epub 2013 Oct 9. [PubMed:24119503]
  4. Chew EY, Clemons TE, Agron E, Sperduto RD, Sangiovanni JP, Kurinij N, Davis MD: Long-term effects of vitamins C and E, beta-carotene, and zinc on age-related macular degeneration: AREDS report no. 35. Ophthalmology. 2013 Aug;120(8):1604-11.e4. doi: 10.1016/j.ophtha.2013.01.021. Epub 2013 Apr 10. [PubMed:23582353]
  5. Traber MG, Atkinson J: Vitamin E, antioxidant and nothing more. Free Radic Biol Med. 2007 Jul 1;43(1):4-15. doi: 10.1016/j.freeradbiomed.2007.03.024. Epub 2007 Mar 31. [PubMed:17561088]
  6. Qureshi AA, Khan DA, Silswal N, Saleem S, Qureshi N: Evaluation of Pharmacokinetics, and Bioavailability of Higher Doses of Tocotrienols in Healthy Fed Humans. J Clin Exp Cardiolog. 2016 Apr;7(4). doi: 10.4172/2155-9880.1000434. Epub 2016 Apr 28. [PubMed:27493840]
  7. Brigelius-Flohe R, Traber MG: Vitamin E: function and metabolism. FASEB J. 1999 Jul;13(10):1145-55. [PubMed:10385606]
  8. 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]
  9. Zondlo Fiume M: Final report on the safety assessment of Tocopherol, Tocopheryl Acetate, Tocopheryl Linoleate, Tocopheryl Linoleate/Oleate, Tocopheryl Nicotinate, Tocopheryl Succinate, Dioleyl Tocopheryl Methylsilanol, Potassium Ascorbyl Tocopheryl Phosphate, and Tocophersolan. Int J Toxicol. 2002;21 Suppl 3:51-116. doi: 10.1080/10915810290169819. [PubMed:12537931]
  10. FDA Code of Federal Regulations [Link]
  11. National Institute for Health [Link]
  12. Researchgate [Link]
External Links
PubChem Substance
347911165
Wikipedia
Tocopherol
ATC Codes
A11HA03 — Tocopherol (vit e)
MSDS
Download (1.3 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentAllergic Rhinitis (AR) / Mild Asthma1
2Unknown StatusTreatmentFibrosis1
2WithdrawnTreatmentOral Mucositis1
3RecruitingTreatmentAvascular Necrosis / Bisphosphonate-related Osteonecrosis of the Jaw / Medication-related Osteonecrosis of the Jaw1
3TerminatedTreatmentChronic Hepatitis C Virus (HCV) Infection / Fibrosis, Liver1
3Unknown StatusTreatmentAlzheimer's Disease (AD) / Down Syndrome (DS)1
4CompletedTreatmentOsteoradionecrosis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
LiquidTopical
PatchTopical
LotionTopical
Kit
SoapTopical1.1 g/100g
CreamTopical0.0032 g/100g
Solution / dropsOral
LiquidOral
Capsule, gelatin coatedOral
EmulsionTopical
Tablet, coatedOral
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
PropertyValueSource
boiling point (°C)Decomposes'MSDS'
water solubilityInsoluble'MSDS'
Predicted Properties
Not Available
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Targets

1. Free radicals
Kind
Group
Organism
Human
Pharmacological action
Yes
Actions
Binder
References
  1. Traber MG, Atkinson J: Vitamin E, antioxidant and nothing more. Free Radic Biol Med. 2007 Jul 1;43(1):4-15. doi: 10.1016/j.freeradbiomed.2007.03.024. Epub 2007 Mar 31. [PubMed:17561088]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
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. 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 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]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Binder
General Function
Very-low-density lipoprotein particle receptor activity
Specific Function
Binds VLDL and transports it into cells by endocytosis. In order to be internalized, the receptor-ligand complexes must first cluster into clathrin-coated pits. Binding to Reelin induces tyrosine p...
Gene Name
VLDLR
Uniprot ID
P98155
Uniprot Name
Very low-density lipoprotein receptor
Molecular Weight
96097.45 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]
2. High density lipoprotein
Kind
Protein group
Organism
Human
Pharmacological action
No
Actions
Binder
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
Binder
General Function
Virus receptor activity
Specific Function
Binds LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis. In order to be internalized, the receptor-ligand complexes must first cluster into clat...
Gene Name
LDLR
Uniprot ID
P01130
Uniprot Name
Low-density lipoprotein receptor
Molecular Weight
95375.105 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
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
Transporter
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]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Transporter
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
Transporter
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. 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 December 03, 2015 09:51 / Updated on August 02, 2018 06:22