Clinical TrialsVitamin E Supplementation and Hepatic Drug Metabolism in HumansClarke, Michael W PhD*†; Burnett, John R MD, PhD*†; Wu, Jason H Y PhD†; Hodgson, Jonathan M PhD†; Ledowski, Thomas MD†‡; Puddey, Ian B MD†; Croft, Kevin D PhD†Author Information From the *Department of Core Clinical Pathology and Biochemistry, PathWest Laboratory Medicine, Royal Perth Hospital; †School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia; and ‡Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, Perth, Western Australia, Australia. Received for publication April 15, 2009; accepted July 25, 2009. The authors report no conflicts of interest. Reprints: Dr. Michael W. Clarke, PhD, Department of Core Clinical Pathology and Biochemistry, PathWest Laboratory Medicine, Royal Perth Hospital, University of Western Australia, Perth, Western Australia 6000, Australia (e-mail: Michael.W.Clarke@health.wa.gov.au). Journal of Cardiovascular Pharmacology: December 2009 - Volume 54 - Issue 6 - p 491-496 doi: 10.1097/FJC.0b013e3181bfae18 Buy Metrics Abstract Meta-analyses studies suggest that high-dose vitamin E may be associated with increased mortality in some populations. Vitamin E may increase the production of CYP3A4 in the liver, and this could lead to an increase in drug metabolism, potentially lowering the efficacy of therapeutic drugs. We hypothesized that upregulation of CYP3A4 by α-tocopherol (α-TOH) would decrease the plasma concentration of the CYP3A4 substrate midazolam. Baseline metabolism of midazolam (1 mg intravenously) was determined in 12 healthy subjects before randomization into 2 groups of 6 to receive either RRR-α-TOH (750 IU/d) or placebo for 3 weeks. At completion, subjects were given an additional 1 mg intravenous bolus of midazolam. Plasma midazolam, 1-hydroxy-midazolam, and urinary α-TOH metabolite excretion were measured using gas chromatography mass spectrometry. Serum α-TOH was measured using high performance liquid chromatography with electrochemical detection. Serum α-TOH increased by 100% (P = 0.002) and urinary α-TOH metabolite excretion increased 20-fold in the treatment group versus placebo (P = 0.001). There was no effect on the area under time curve of midazolam in subjects taking α-TOH compared with placebo. These findings do not support the hypothesis that α-TOH supplementation interferes with hepatic CYP3A4-mediated drug metabolism. © 2009 Lippincott Williams & Wilkins, Inc.