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

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Web End = Cancer Chemother Pharmacol (2016) 78:157165

DOI 10.1007/s00280-016-3048-0

ORIGINAL ARTICLE

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Web End = Pharmacokinetics and safety of vitamin E tocotrienol after single and multiple doses in healthy subjectswith measurement of vitamin E metabolites

Amit Mahipal1 Jason Klapman1 Shivakumar Vignesh2 Chung S. Yang3 Anthony Neuger4 DungTsa Chen5 Mokenge P. Malafa1

Abstract

Purpose Vitamin E delta-tocotrienol (VEDT) has demonstrated chemopreventive and antineoplastic activity in pre-clinical 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 49.3 and 4.77.3 h,

* Mokenge P. Malafa [email protected]

1 Department of Gastrointestinal Oncology, H. Lee Moftt Cancer Center and Research Institute, 12902 Magnolia Drive FOB-2, Tampa, FL 33612, USA

2 Division of Gastroenterology and Hepatology, SUNY Health Sciences Center at Brooklyn, Brooklyn, NY 11203, USA

3 Department of Chemical Biology, Ernest Mario Schoolof Pharmacy, Rutgers, The State University of New Jersey, Piscataway Township, NJ, USA

4 Translational Research Core, H. Lee Moftt Cancer Center and Research Institute, Tampa, FL, USA

5 Department of Biostatistics and Bioinformatics, H. Lee Moftt Cancer Center and Research Institute, Tampa, FL, USA

Received: 1 October 2015 / Accepted: 26 April 2016 / Published online: 8 June 2016 Springer-Verlag Berlin Heidelberg 2016

maximum concentration of 795.63742.6 and 493.3 3746 ng/mL, half-life of 1.75.9 and 2.36.9 h, and 012 h area under the curve of 4518.720,781.4 and 1987.7 22,171.2 ng h/mL. Plasma tocotrienols were signicantly increased after VEDT administration, indicating oral bio-availability of VEDT in humans. Plasma and urine levels of metabolites,...