title: Safety data on 19 vehicles for use in 1 month oral rodent pre-clinical studies: administration of hydroxypropyl-ß-cyclodextrin causes renal toxicity.
abstract: Potential new drugs are assessed in pre-clinical in vivo studies to determine their safety profiles. The drugs are formulated in vehicles suitable for the route of administration and the physicochemical properties of the drug, aiming to achieve optimal exposure in the test species. The availability of safety data on vehicles is often limited (incomplete data, access restricted/private databases). Nineteen potentially useful vehicles that contained new and/or increased concentrations of excipients and for which little safety data have been published were tested. Vehicles were dosed orally once daily to HanWistar rats for a minimum of 28 days and a wide range of toxicological parameters were assessed. Only 30% (w/v) hydroxypropyl-ß-cyclodextrin was found unsuitable owing to effects on liver enzymes (AST, ALT and GLDH), urinary volume and the kidneys (tubular vacuolation and tubular pigment). 20% (v/v) oleic acid caused increased salivation and hence this vehicle should be used with caution. As 40% (v/v) tetraethylene glycol affected urinary parameters, its use should be carefully considered, particularly for compounds suspected to impact the renal system and studies longer than 1 month. There were no toxicologically significant findings with 10% (v/v) dimethyl sulphoxide, 20% (v/v) propylene glycol, 33% (v/v) Miglyol®812, 20% (w/v) Kolliphor®RH40, 10% (w/v) Poloxamer 407, 5% (w/v) polyvinylpyrrolidone K30 or 10% (v/v) Labrafil®M1944. All other vehicles tested caused isolated or low magnitude effects which would not prevent their use. The aim of sharing these data, including adverse findings, is to provide meaningful information for vehicle selection, thereby avoiding repetition of animal experimentation.
authors.affiliation: AstraZeneca, Drug Safety and Metabolism, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
authors.forename: Guy
authors.initials: G
authors.lastname: Healing
authors.affiliation: AstraZeneca, Pharmaceutical Development, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
authors.forename: Tabassum
authors.initials: T
authors.lastname: Sulemann
authors.affiliation: AstraZeneca, Drug Safety and Metabolism, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Cotton
authors.affiliation: AstraZeneca, Drug Safety and Metabolism, 310 Darwin Building, Science Park, Cambridge, CB40 0WG, UK.
authors.forename: Jayne
authors.initials: J
authors.lastname: Harris
authors.affiliation: AstraZeneca, Drug Safety and Metabolism, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Hargreaves
authors.affiliation: AstraZeneca, Drug Safety and Metabolism, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
authors.forename: Rowena
authors.initials: R
authors.lastname: Finney
authors.affiliation: AstraZeneca, Discovery Sciences, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kirk
authors.affiliation: AstraZeneca, Drug Safety and Metabolism, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
authors.forename: Carolin
authors.initials: C
authors.lastname: Schramm
authors.affiliation: AstraZeneca, Drug Safety and Metabolism, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Garner
authors.affiliation: AstraZeneca, Pharmaceutical Development, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
authors.forename: Perrine
authors.initials: P
authors.lastname: Pivette
authors.affiliation: AstraZeneca, Drug Safety and Metabolism, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Burdett
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D004121:Dimethyl Sulfoxide / Q000633:toxicity; D005026:Ethylene Glycols / Q000633:toxicity; D005260:Female; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D014677:Pharmaceutical Vehicles / Q000633:toxicity*; D020442:Poloxamer / Q000633:toxicity; D019946:Propylene Glycol / Q000633:toxicity; D051381:Rats; D014280:Triglycerides / Q000633:toxicity; D047392:beta-Cyclodextrins / Q000633:toxicity*
chemical_list: D005026:Ethylene Glycols; D014677:Pharmaceutical Vehicles; D014280:Triglycerides; D047392:beta-Cyclodextrins; D020442:Poloxamer; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C022834:miglyol 812; D019946:Propylene Glycol; C010111:carbitol; D004121:Dimethyl Sulfoxide
keywords: Excipient; Hydroxypropyl-cyclodextrin; Rodent; Safety data; Toxicology; Vehicle; drug development; formulation; pre-clinical; renal toxicity