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

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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 ID
27493840 [ View in PubMed
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Abstract

BACKGROUND: Tocotrienols has been known to lower serum lipid parameters below 500 mg/d, while increase lipid parameters at higher dose of 750 mg/d. delta-Tocotrienol has a novel inflammatory property of concentration-dependent inhibition and activation. Therefore, inhibition (anti-inflammatory) property of tocotrienols at low doses is useful for cardiovascular disease, whereas, activation (pro-inflammatory) property using high dose is found effective for treatments of various types of cancer. We have recently described plasma bioavailability of 125 mg/d, 250 mg/d and 500 mg/d doses of delta-tocotrienol in healthy fed subjects, which showed dose-dependent increases in area under the curve (AUC) and maximum concentration (Cmax). Hence, in the current study, higher doses of tocotrienols have used to analyze its effect on plasma pharmacokinetic parameters. AIMS: To evaluate the safety and bioavailability of higher doses (750 mg and 1000 mg) of annatto-based tocotrienols in healthy fed subjects. All four isomers (alpha-, beta-, gamma-, delta-) of tocols (tocotrienols and tocopherols) present in the plasmas of subjects were quantified and analyzed for various pharmacokinetic parameters. STUDY DESIGN: An open-label, randomized study was performed to analyze pharmacokinetics and bioavailability of delta-tocotrienol in 6 healthy fed subjects. All subjects (3/dose) were randomly assigned to one of each dose of 750 mg or 1000 mg. Blood samples were collected at 0, 1, 2, 4, 6, 8 h intervals and all isomers of alpha-,beta-,gamma-,delta-tocotrienols, and tocopherols in plasmas were quantified by HPLC. RESULTS: Oral administration of 750 and 1000 mg/d of tocotrienols resulted in dose-dependent increases in plasmas (ng/ml) AUCt0-t8 6621, 7450; AUCt0-infinity 8688, 9633; AUMC t0-infinity 52497, 57199; MRT 6.04, 5.93; Cmax 1444, 1592 (P<0.05), respectively, of delta-tocotrienol isomer. Moreover, both doses also resulted in plasmas Tmax 3.33-4 h; elimination half-life (t1/2 h) 2.74, 2.68; time of clearance (Cl-T, l/h) 0.086, 0.078; volume of distribution (Vd/f, mg/h) 0.34, 0.30; and elimination rate constant (ke; h(-1)) 0.25, 0.17, respectively of delta- tocotrienol isomer. Similar results of these parameters were reported for gamma-tocotrienol, beta- tocotrienol, alpha-tocotrienol, delta-tocopherol, gamma-tocopherol, and beta-tocopherol, except for alpha- tocopherol. CONCLUSIONS: This study has described pharmacokinetics using higher doses of 750 mg/d and 1000 mg/d of delta-tocotrienol. These results confirmed earlier findings that Tmax was 3-4 h for all isomers of tocotrienols and tocopherols except for alpha-tocopherol (6 h). These higher doses of tocotrienols were found safe in humans and may be useful for treatments of various types of cancer, diabetes, and Alzheimer's disease.

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