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.

A vitamin B-12 supplement of 500 µg/d for eight weeks does not normalize urinary methylmalonic acid or other biomarkers of vitamin B-12 status in elderly people with moderately poor vitamin B-12 status.

Plasma vitamin B-12 is the most commonly used biomarker of vitamin B-12 status, but the predictive value for low vitamin B-12 status is poor. The urinary methylmalonic acid (uMMA) concentration has potential as a functional biomarker of vitamin B-12 status, but the response to supplemental vitamin B-12 is uncertain. A study was conducted to investigate the responsiveness of uMMA to supplemental vitamin B-12 in comparison with other biomarkers of vitamin B-12 status [plasma vitamin B-12, serum holotranscobalamin (holoTC), plasma MMA] in elderly people with moderately poor vitamin B-12 status. A double-blind, placebo-controlled, randomized 8-wk intervention study was carried out using vitamin B-12 supplements (500 µg/d, 100 µg/d, and 10 µg/d cyanocobalamin) in 100 elderly people with a combined plasma vitamin B-12 <250 pmol/L and uMMA ratio (µmol MMA/mmol creatinine) >1.5. All biomarkers had a dose response to supplemental vitamin B-12. Improvements in plasma vitamin B-12 and serum holoTC were achieved at cobalamin supplements of 10 µg/d, but even 500 µg/d for 8 wk did not normalize plasma vitamin B-12 in 8% and serum holoTC in 12% of people. The response in uMMA was comparable with plasma MMA; 15-25% of people still showed evidence of metabolic deficiency after 500 µg/d cobalamin for 8 wk. There was a differential response in urinary and plasma MMA according to smoking behavior; the response was enhanced in ex-smokers compared with never-smokers. uMMA offers an alternative marker of metabolic vitamin-B12 status, obviating the need for blood sampling.

Determinants of urinary methylmalonic acid concentration in an elderly population in the United Kingdom.

BACKGROUND: An age-related deterioration of vitamin B-12 status has been well documented. The early detection of deficiency may prevent the development of serious clinical symptoms, but plasma vitamin B-12 concentration is known to be an imperfect measure of vitamin B-12 status. Urinary methylmalonic acid (MMA) may be a more informative biomarker of vitamin B-12 status; however, biochemical, dietary, and other lifestyle determinants are not known. OBJECTIVE: We identified determinants of urinary MMA concentrations in free-living men and women aged ≥65 y in the United Kingdom. DESIGN: A cross-sectional study in 591 men and women aged 65-85 y, with no clinical evidence of vitamin B-12 deficiency, was conducted to determine the demographic, clinical, and lifestyle determinants of urinary MMA concentration expressed as the ratio of micromoles of MMA to millimoles of creatinine (uMMA ratio). RESULTS: Twenty percent of subjects had plasma vitamin B-12 concentrations <200 pmol/L. Seventeen percent of the variation in the uMMA ratio could be explained by plasma holotranscobalamin and sex; total vitamin B-12 intake and measures of renal function and gastric function made only a small contribution to the model. The uMMA ratio was lower in people with moderately impaired renal function. CONCLUSIONS: Plasma holotranscobalamin and sex were the most important determinants of uMMA ratio in elderly people with no clinical diagnosis of renal impairment. This biomarker might underestimate vitamin B-12 deficiency in a population in which renal impairment is prevalent. This trial was registered at www.controlled-trials.com as ISRCJN83921062.