title: D-α-tocopheryl polyethylene glycol 1000 succinate-containing vehicles provide no detectable chemoprotection from oxidative damage.
abstract: The objective of this study was to evaluate potential protective effects of vehicles containing d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), which may impact nonclinical safety assessments of oxidative processes. This was achieved by evaluating plasma, liver and adrenal gland concentrations of d-α-tocopheryl succinate (TS) and d-α-tocopherol as well as oxidative status of plasma following oral dosing of TPGS-containing vehicles, intraperitoneal (IP) dosing of TS or ex vivo treatment of blood with H2O2. Male and female rats were dosed orally with formulations containing 5% or 40% TPGS (70 or 550 mg kg(-1) day(-1) TS, respectively) for 1 week. A control group was dosed orally with polyethylene glycol-400 (PEG-400; no vitamin E) and positive control animals received a single 100 mg kg(-1) day(-1) IP injection of TS. Whole blood from untreated animals was treated ex vivo with 5 or 50 mm H(2)O(2), with or without TS (0.5, 5, 50 or 500 μm) or ascorbate (1 mm), for 1 h. Oral TPGS treatments did not affect d-α-tocopherol 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 in all other groups. Oral administration of TPGS did not reduce plasma lipid peroxidation in vivo. Substantially greater TS concentrations used ex vivo (100× greater than in vivo) were also unable to reduce lipid peroxidation in H2O2 -treated whole blood. These results provide evidence that administration of oral TPGS vehicles is unlikely to impact nonclinical safety assessments of pharmaceuticals.
authors.affiliation: Bristol-Myers Squibb, Drug Safety Evaluation, Mt. Vernon, IN, 47620, USA.
authors.forename: Bethany R
authors.initials: BR
authors.lastname: Baumgart
authors.affiliation: Bristol-Myers Squibb, Drug Safety Evaluation, Mt. Vernon, IN, 47620, USA.
authors.forename: Terry R
authors.initials: TR
authors.lastname: Van Vleet
authors.affiliation: Bristol-Myers Squibb, Drug Safety Evaluation, Mt. Vernon, IN, 47620, USA.|Johnson & Johnson, Springhouse, PA, 19477, USA.
authors.forename: Damir
authors.initials: D
authors.lastname: Simic
authors.affiliation: Bristol-Myers Squibb, Drug Safety Evaluation, New Brunswick, NJ, 08903, USA.
authors.forename: Theodora W
authors.initials: TW
authors.lastname: Salcedo
authors.affiliation: Bristol-Myers Squibb, Pharmaceutical Candidate Optimization, Wallingford, CT, 06492, USA.|Bristol-Myers Squibb, Pharmaceutical Candidate Optimization, Pennington, NJ, 08534, USA.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Lentz
authors.affiliation: Bristol-Myers Squibb, Pharmaceutical Candidate Optimization, Wallingford, CT, 06492, USA.|WIL Research, Ashland, OH, 44805, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Donegan
authors.affiliation: Bristol-Myers Squibb, Drug Safety Evaluation, Lawrenceville, NJ, 08543, USA.
authors.forename: Marc H
authors.initials: MH
authors.lastname: Davies
authors.affiliation: Bristol-Myers Squibb, Drug Safety Evaluation, Mt. Vernon, IN, 47620, USA.
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bunch
authors.affiliation: Bristol-Myers Squibb, Drug Safety Evaluation, Mt. Vernon, IN, 47620, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Sanderson
authors.affiliation: Bristol-Myers Squibb, Drug Safety Evaluation, Mt. Vernon, IN, 47620, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Lange
mesh_terms: D000311:Adrenal Glands / Q000737:chemistry; D000818:Animals; D004337:Drug Carriers / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D008099:Liver / Q000737:chemistry; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D011092:Polyethylene Glycols / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013858:Thiobarbiturates / Q000494:pharmacology; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D024502:alpha-Tocopherol / Q000032:analysis / Q000097:blood
chemical_list: D004337:Drug Carriers; D013858:Thiobarbiturates; D014810:Vitamin E; D011092:Polyethylene Glycols; D024502:alpha-Tocopherol; C029684:thiobarbituric acid; C014225:tocophersolan
keywords: TPGS; malondialdehyde; oxidative stress; tocopherol; tocopheryl succinate; vehicle