Pharmacokinetics and safety of vitamin E δ-tocotrienol after single and multiple doses in healthy subjects with measurement of vitamin E metabolites.
OBJECTIVE
Vitamin E delta-tocotrienol (VEDT) has demonstrated chemopreventive and antineoplastic activity in preclinical models. The aim of our study was to determine the safety and pharmacokinetics of VEDT and its metabolites after single- and multiple-dose administrations in healthy subjects.


METHODS
Thirty-six subjects received from 100 to 1600 mg of oral VEDT as a single dose or twice daily for 14 consecutive days. A 3 + 3 dose escalation design was utilized. Pharmacokinetic data were derived from high-performance liquid chromatography (HPLC) assays. Serial blood and urine samples were collected before and during VEDT administration, with serum and urine metabolites assessed using HPLC.


RESULTS
No drug-related adverse events were observed. Pharmacokinetic parameters for single and multiple doses were, respectively, as follows (shown as range): time to maximum concentration of 4-9.3 and 4.7-7.3 h, maximum concentration of 795.6-3742.6 and 493.3-3746 ng/mL, half-life of 1.7-5.9 and 2.3-6.9 h, and 0-12 h area under the curve of 4518.7-20,781.4 and 1987.7-22,171.2 ng h/mL. Plasma tocotrienols were significantly increased after VEDT administration, indicating oral bioavailability of VEDT in humans. Plasma and urine levels of metabolites, δ-carboxyethyl hydroxychroman, and δ-carboxymethylbutyl hydroxychroman were elevated after VEDT administration in a dose-dependent manner and were 30-60 times significantly higher than δ-tocotrienol levels. VEDT can be safely administered at doses up to 1600 mg twice daily. Plasma VEDT concentrations were comparable to those obtained in VEDT-treated mice in which tumor growth was delayed.


CONCLUSIONS
Our results suggest that VEDT can be safely consumed by healthy subjects and achieve bioactive levels, supporting the investigation of VEDT for chemoprevention.
Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive FOB-2, Tampa, FL, 33612, USA.
Amit
A
Mahipal
Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive FOB-2, Tampa, FL, 33612, USA.
Jason
J
Klapman
Division of Gastroenterology and Hepatology, SUNY Health Sciences Center at Brooklyn, Brooklyn, NY, 11203, USA.
Shivakumar
S
Vignesh
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway Township, NJ, USA.
Chung S
CS
Yang
Translational Research Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Anthony
A
Neuger
Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Dung-Tsa
DT
Chen
Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive FOB-2, Tampa, FL, 33612, USA. mokenge.malafa@moffitt.org.
Mokenge P
MP
Malafa
D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D013045:Species Specificity; D014810:Vitamin E / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D055815:Young Adult
D000970:Antineoplastic Agents; D014810:Vitamin E; C082097:tocotrienol, delta
Antitumor agent; Biomarker; Chemoprevention; Pancreatic cancer; Tocochromanol