6th Global Summit on Toxicology and Applied Pharmacology
Bristol-Myers Squibb, USA
Title: D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS)-containing vehicles provide no detectable chemoprotection from oxidative damage
Biography: Bethany R Baumgart
Pharmaceutical formulations (vehicles) used to administer test articles to animals often contain excipients to enhance delivery of the test compound. The common excipient d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) increases solubility and maximizes systemic exposure of lipophilic test articles. Given the well established antioxidant properties of d-α-tocopheryl succinate (TS), a component of TPGS, and d-α-tocopherol (TOC), hydrolyzed TS, we examined the potential protective effects of vehicles containing TPGS. Such effects could mask potential toxicities of test articles, including processes involved in carcinogenesis, and impact nonclinical safety assessments. Male and female Sprague-Dawley rats were administered vehicles containing 5% or 40% TPGS (70 or 550 mg/kg/day TS, respectively) orally for 1 week. A control group was administered polyethylene glycol-400 (PEG-400; no vitamin E) orally and positive control animals received a single 100 mg/kg intraperitoneal (IP) injection of TS. Additionally, whole blood from untreated animals was incubated with 5 or 50mM H2O2 ex vivo with or without TS (0.5, 5, 50, or 500μM) or ascorbate (1mM), as a positive control, for 1 hour. Plasma, liver, and adrenal gland concentrations of TS and TOC as well as oxidative status of plasma were evaluated following oral administration of TPGS-containing vehicles, IP injection of TS, or treatment of whole blood with H2O2 ex vivo. Oral TPGS administration did not affect TOC concentrations in plasma or adrenal glands and caused only transient increases in liver. Concentrations of TS in plasma, liver, and adrenal glands were undetectable in control animals, but increased with administration of vehicles containing 5 and 40% TPGS. Oral administration of TPGS did not reduce plasma lipid peroxidation in vivo. Substantially greater TS concentrations (100× greater than in vivo) added to H2O2-treated whole blood ex vivo were also unable to reduce lipid peroxidation. These results provide evidence that administration of oral TPGS vehicles is unlikely to impact nonclinical carcinogenicity safety assessments of pharmaceuticals.