Pharmacokinetics and Bioavailability of Annatto δ-tocotrienol in Healthy Fed Subjects

Abstract

Background: Although, α-tocopherol is the most bioavailable form of vitamin E, but several animal and clinical studies have demonstrated tocotrienol bioavailability to various tissues. There are few reports on bioavailability of tocotrienols in humans. Most studies were carried out with mixtures of tocotrienols + tocopherols rather than pure tocotrienols. Moreover, dietary α-tocopherol interferes with the bioavailability of tocotrienols, and prevents absorption and delivery to organs and tissues.Aim: Pharmacokinetics and bioavailability of annatto-based δ-tocotrienol, plasma levels of α-, β-, γ-, δ-tocotrienol and tocopherols were quantified. In addition, several cytokines and microRNAs were examined. Study design:An open-label, randomized study evaluated pharmacokinetics and bioavailability of δ-tocotrienol in 33 healthy fed subjects. All subjects (11/dose) were randomly assigned to doses of 125, 250, or 500 mg/d. Plasma samples collected at 0, 1, 2, 3, 4, 6, 8, 10 h intervals were estimated by HPLC for tocols (tocotrienols and tocopherols). Results:The present study describes the effects of δ-tocotrienol on pharmacokinetic parameters of all eight tocol isomers. Supplementation of 125, 250 and 500 mg/d doses resulted in dose-dependent increases of (a) area under concentration-time curve (AUC t0 -t10 , ng/ml) 2464, 5412, 14986; (b) maximum concentration (C max , ng/ml) 829, 1920, 3278 (P<0.001); (c) time to achieve maximum peak (T max ; h) 3, 3, 6; (d) elimination of half-life (t 1/2 h) 1.74, 1.39, 2.54; (e) time of clearance (Cl-T, h -1 ) 0.049, 0.045, 0.030; (f) volume of distribution (Vd/f, mg/h) 0.119, 0.114, 0.113; and (g) elimination rate constant (Ke; h -1 ) 0.412, 0.401, 0.265. Similar results were reported for the other tocols. Maximum plasma levels of δ-tocotrienol were observed at 3 h with doses of 125 and 250 mg/d, and 6 h with 500 mg/d. γ-tocotrienol, β-tocotrienol, α-tocotrienol, δ-tocopherol, γ-tocopherol β-tocopherol and α-tocopherol were appeared in the plasma after 2 h. Moreover, δ-tocotrienol treatment resulted in down-regulation of eight cytokines and upregulation of adiponectin, TGF-β1, and leptin. The expression of miR-34a (increased in bipolar disorder) was down-regulated, but expression of miR-107, miR-122a, and miR-132 (decreased in Alzheimer's disease) was upregulated by δ-tocotrienol treatment.Conclusion: This is the first study describing the effect of δ-tocotrienol on pharmacokinetics and bioavailability of all eight tocol isomers. When tocotrienols are supplemented in absence of tocopherols, δ-tocotrienol has better bioavailability, and δ-tocotrienol is converted stepwise to other tocotrienols/tocopherols. These results support that tocotrienol, particularly δ-tocotrienol, as a dietary supplement might be useful in the prevention of age-related and chronic ailments. Pharmacokinetics and Bioavailability of Annatto δ-tocotrienol in Healthy Fed Subjects IntroductionSeveral studies have reported the antioxidant, anti-inflammatory, anticancer, hypocholesterolemic and neuroprotec...

Evaluation of Pharmacokinetics, and Bioavailability of Higher Doses of Tocotrienols in Healthy Fed Humans

“…Six healthy subjects (n=3/dose) were selected for the present study. A small number of subjects were used due to results of our earlier study of 11 subjects/dose were very consistent and there was not much variation (<5.0%) between different subjects of the same group [ 1 ]. The study was conducted in accordance with the current Good Clinical Practices (FDA, 1996) and the Declaration of Helsinki (WMA, 2008).…”

“…We have recently reported the pharmacokinetic and bioavailability of various doses (125 mg, 250 mg, and 500 mg) of δ-tocotrienol in 11 fed healthy participants/group (n=33). This was the first study which demonstrated the effect of δ-tocotrienol on several pharmacokinetic parameters of all eight isomers of tocol family (α-, β-, γ-, δ-tocotrienols and α-, β-, γ-, δ- tocopherols) [ 1 ]. Our data showed that in plasmas of healthy subjects, δ-tocotrienol bioavailability resulted in dose-dependent increase in area under the curve (AUC) and maximum concentration (C max ).…”

“…Our data showed that in plasmas of healthy subjects, δ-tocotrienol bioavailability resulted in dose-dependent increase in area under the curve (AUC) and maximum concentration (C max ). The time to achieve maximum peak (T max ) varied between 3-4 h for isomers of tocotrienols and 3-6 h for isomers of tocopherols at 125 mg, 250 mg, 500 mg doses, indicating the longer time of excretion for tocopherols compared to tocotrienols that showed better bioavailability of tocotrienols than tocopherols [ 1 ]. The present study is the extension of this study, using higher doses of 750 mg and 1000 mg of tocotrienols.…”

“…Tocotrienols group had plasma T max (2–3 h) and α-tocopherol group had plasma T max (3–5 h). None of the published studies have reported the bioavailability of β-, γ-, δ-tocopherol other than our recently published study describing the pharmacokinetic, bioavailability and absorption of all four isomers of tocotrienols and tocopherols [ 1 ]. As reported earlier, the doses below 500 mg/d of α-tocotrienol are effective in lowering lipid parameters by decreasing the level of several lipid parameters while, doses greater than 500 mg/d of δ-tocotrienol (750 mg/d) possibly kill cancer cells [ 3 - 5 ].…”

Potential Role of Tocotrienols on Non-Communicable Diseases: A Review of Current Evidence

“…These findings indicated that the consumption of food increased the onset and extent of T3 absorption [18]. Qureshi and colleagues reported that participants supplemented orally with annatto T3 after heavy breakfast achieved peak plasma concentration for all T3 isomers (αT3, βT3, γT3, and δT3) after 3 h of oral administration [19,20]. For parenteral administration, single subcutaneous (s.c.) injection of 300 mg/kg δT3 was given to the CD2F1 mice and the bioavailability of δT3 was assessed.…”