Pharmacokinetics and safety of vitamin E δ-tocotrienol after single and multiple doses in healthy subjects with measurement of vitamin E metabolites

• Published in: Cancer chemotherapy and pharmacology Vol. 78; no. 1; pp. 157 - 165
• Main Authors: Mahipal, Amit, Klapman, Jason, Vignesh, Shivakumar, Yang, Chung S., Neuger, Anthony, Chen, Dung-Tsa, Malafa, Mokenge P.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.07.2016
• Subjects: Adult; Animals; antineoplastic activity; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Area Under Curve; bioavailability; blood serum; Cancer Research; chemoprevention; Chromatography, High Pressure Liquid - methods; delta-tocotrienol; dose response; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Half-Life; high performance liquid chromatography; Humans; Male; Medicine; Medicine & Public Health; metabolites; Mice; Middle Aged; neoplasms; Oncology; Original Article; pharmacokinetics; Pharmacology/Toxicology; Species Specificity; urine; Vitamin E - administration & dosage; Vitamin E - adverse effects; Vitamin E - analogs & derivatives; Vitamin E - pharmacokinetics; Young Adult; Biomarker; Tocochromanol; Antitumor agent; Chemoprevention; Pancreatic cancer
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-016-3048-0

Purpose 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.