title: Evaluation of Pharmacokinetics, and Bioavailability of Higher Doses of Tocotrienols in Healthy Fed Humans.
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. δ-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 δ-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.
  
  
  OBJECTIVE
  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 (α-, β-, γ-, δ-) of tocols (tocotrienols and tocopherols) present in the plasmas of subjects were quantified and analyzed for various pharmacokinetic parameters.
  
  
  METHODS
  An open-label, randomized study was performed to analyze pharmacokinetics and bioavailability of δ-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 α-,β-,γ-,δ-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-t86621, 7450; AUCt0-∞8688, 9633; AUMC t0-∞52497, 57199; MRT 6.04, 5.93; Cmax1444, 1592 (P<0.05), respectively, of δ-tocotrienol isomer. Moreover, both doses also resulted in plasmas Tmax3.33-4 h; elimination half-life (t1/2h) 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 δ- tocotrienol isomer. Similar results of these parameters were reported for γ-tocotrienol, β- tocotrienol, α-tocotrienol, δ-tocopherol, γ-tocopherol, and β-tocopherol, except for α- tocopherol.
  
  
  CONCLUSIONS
  This study has described pharmacokinetics using higher doses of 750 mg/d and 1000 mg/d of δ-tocotrienol. These results confirmed earlier findings that Tmaxwas 3-4 h for all isomers of tocotrienols and tocopherols except for α-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.
authors: Department of Basic Medical Sciences, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO 64108, USA.
authors: Asaf A
authors: AA
authors: Qureshi
authors: Department of Chemical Pathology and Endocrinology, Armed Forces Institute of Pathology, and National University of Medical Science, Rawalpindi, 64000, Pakistan.
authors: Dilshad A
authors: DA
authors: Khan
authors: Department of Basic Medical Sciences, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO 64108, USA.
authors: Neerupma
authors: N
authors: Silswal
authors: Pakistan Ordinance Factory Hospital, Wah Cantt, Rawalpindi, 64000, Pakistan.
authors: Shahid
authors: S
authors: Saleem
authors: Department of Basic Medical Sciences, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO 64108, USA; Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri- Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA.
authors: Nilofer
authors: N
authors: Qureshi
keywords: AUMC; Annatto-based δ-tocotrienol; Bioavailability of AUC; Cl/h; Cmax; MRT; Tmax; Tocopherols; Tocotrienols; Vd/l; t1/2