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General Description:

Tocopherol, identified by CAS number 1406-66-2, is a notable compound with significant therapeutic applications. 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. It is currently under the list of substances generally recognized as safe (GRAS) in the FDA for the use of human consumption.

Indications:

This drug is primarily indicated for: Tocopherol can be used as a dietary supplement for patients with a deficit of vitamin E; this is mainly prescribed in the alpha form. 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. Tocopherol, due to its antioxidant properties, is studied for its use in prevention or treatment in different complex diseases such as cancer, atherosclerosis, cardiovascular diseases, and age-related macular degeneration. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Tocopherol undergoes metabolic processing primarily in: Excess tocopherol is converted into their corresponding carboxyethylhydroxychroman (CEHC), based on the isomer of tocopherol. 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. 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. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Tocopherol are crucial for its therapeutic efficacy: The absorption of tocopherol in the digestive tract requires the presence of fat. 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 C_max was 1353.79 ng/ml for δ-tocopherol, 547.45 ng/ml for γ-tocopherol, 704.16 ng/ml for β-tocopherol, and 2754.36 ng/ml for α-tocopherol. The T_max is three to four hours for δ-tocopherol, γ-tocopherol, and β-tocopherol and about six hours for α-tocopherol. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Tocopherol is an important consideration for its dosing schedule: The elimination half-life ranged from 2.44 to 3.02 hours for δ-tocopherol, γ-tocopherol, and β-tocopherol. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Tocopherol exhibits a strong affinity for binding with plasma proteins: 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. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Tocopherol from the body primarily occurs through: The pharmacokinetic profile of tocopherol indicates a longer time of excretion for tocopherols when compared to tocotrienols. The different conjugated metabolites are excreted in the urine or feces depending on the length of their side-chain. 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. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Tocopherol is distributed throughout the body with a volume of distribution of: The apparent volume of distribution was 0.284 ± 0.021 mL for δ-tocopherol, 0.799 ± 0.047 mL for γ-tocopherol, and 0.556 ± 0.046 mL for β-tocopherol. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Tocopherol is a critical factor in determining its safe and effective dosage: Clearance ranged from 0.081 to 0.190 L/h for δ-tocopherol, γ-tocopherol, and β-tocopherol. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Tocopherol exerts its therapeutic effects through: 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. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Tocopherol functions by: 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. 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. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Tocopherol is categorized under the following therapeutic classes: Alimentary Tract and Metabolism, Antioxidants, Benzopyrans, Biological Factors, Compounds used in a research, industrial, or household setting, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Substrates, Diet, Food, and Nutrition, Drugs that are Mainly Renally Excreted, Food, Heterocyclic Compounds, Fused-Ring, Micronutrients, Physiological Phenomena, Protective Agents, Pyrans, Vitamin E, Vitamins, Vitamins (Fat Soluble). These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Tocopherol include:

• Water Solubility: Insoluble
• Boiling Point: Decomposes