Safety data on 19 vehicles for use in 1 month oral rodent pre-clinical studies: administration of hydroxypropyl-ß-cyclodextrin causes renal toxicity.

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.

Evaluation of novel urinary renal biomarkers with a cisplatin model of kidney injury: effects of collection period.

A number of novel urinary biomarkers have been identified and partially qualified for use as markers for renal injury in rats. To date, all evaluation studies have been made using 18 to 24 hour collection periods. However, shorter, more welfare friendly, urine collection periods are also used in industry. In this article, we quantify urinary biomarker concentration in serial paired sequential short and long urine collections from male rats administered varying concentrations of cisplatin. We calculate the rate of biomarker excretion in normal animals for both collection periods and the bias and correlation in urinary biomarker concentration between collection periods in dosed and control animals, and we estimate the level of agreement in biomarker concentration between both collection periods. We conclude that although there are minor differences in the concentration of some urinary biomarkers that are dependent upon the time and duration of collection, shorter collection protocols do not influence subsequent interpretation of normalized urinary biomarker data for most biomarkers.

Evaluation of novel urinary renal biomarkers: biological variation and reference change values.

A number of novel urinary biomarkers have been identified and partially qualified for use as markers for renal injury in rats. We used two multiplex assays for these novel biomarkers to quantify biomarker concentration in serial urine collections from rats of both sexes administered varying concentrations of cisplatin. From these data, we calculate inter-individual variation and reference ranges from predose animals and intra-individual variation and reference change values from undosed control animals. The biomarkers evaluated are albumin, α glutathione s-transferase, glutathione S-transferase-yb1, lipocalin-2, kidney injury molecule-1, osteopontin, and renal papillary antigen 1. For any creatinine-corrected novel biomarkers, we found intra-individual variation to be no greater than 44% and inter-individual variation to be no greater than 46%. Reference change values for most corrected analytes (except osteopontin) were 50-100%, indicating that a >100% increase in analyte concentration between serial samples would be unlikely to be associated with inherent analytical or biological variation.