GlaxoSmithKline Research and Development; Safety Assessment, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
Int J Toxicol. 2013 May-Jun;32(3):189-97. doi: 10.1177/1091581813485452. Epub 2013 Apr 24.
When conventional vehicles (eg, methylcellulose and water) impart inadequate physical, chemical, and/or biological properties for proper toxicological assessment of test article formulations, nonconventional vehicles may be considered. Often toxicity data for nonconventional vehicle formulations are limited. Studies were conducted to collect toxicity data from a rodent and a non-rodent species given 2 nonconventional vehicles, Solutol HS15/polyethylene glycol (PEG) 400 and Cremophor RH40/PEG 400, with differing formulations and dose volumes (10 mL/kg for rats; 2 or 5 mL/kg for dogs). In rats, both vehicles caused increase in kidney weights (males only) and decrease in thymic weights (males only) without concurrent microscopic findings; altered urine electrolytes, minimally decreased serum electrolytes (males only), and increased serum total cholesterol (females only) were also present. The Cremophor formulation was also associated with increased serum urea (males only) and urine phosphorus: creatinine. For rats given the Solutol formulation, both genders had decreased urine glucose parameters and males had increased urine volume. In dogs, loose/watery feces and emesis were present given either vehicle, and mucus-cell hyperplasia of the ileum was present given the Solutol formulation. Increased red blood cell mass and decreased urine volume in dogs given 30% Solutol/70% PEG 400 (5 mL/kg/d) were likely due to subclinical dehydration and hemoconcentration. For the Cremophor formulations, dose volume-dependent increased incidence of minimal subepithelial gastric hemorrhage was noted in dogs, and dogs given 5 mL/kg/d showed increased serum urea nitrogen. Overall, regardless of the formulation or dose volume, neither vehicle produced overt toxicity in either species, but the Solutol formulation produced fewer effects in rats. Generally, lower dose volumes minimized the severity and/or incidence of findings.
当常规载体（例如甲基纤维素和水）不能为测试制剂的适当毒理学评估提供足够的物理、化学和/或生物学性质时，可以考虑使用非常规载体。通常，非常规载体制剂的毒性数据有限。本研究旨在收集两种非常规载体，即 Solutol HS15/聚乙二醇（PEG）400 和 Cremophor RH40/PEG 400，在不同配方和剂量体积（大鼠为 10 mL/kg；狗为 2 或 5 mL/kg）下，给予啮齿动物和非啮齿动物物种的毒性数据。在大鼠中，两种载体均导致肾脏重量增加（仅雄性）和胸腺重量减少（仅雄性），但无显微镜下发现；还存在尿液电解质改变、血清电解质轻度减少（仅雄性）和血清总胆固醇增加（仅雌性）。Cremophor 制剂还与血清尿素（仅雄性）和尿液磷：肌酐增加有关。对于给予 Solutol 制剂的大鼠，两性的尿液葡萄糖参数均降低，雄性的尿液量增加。在狗中，给予两种载体均出现稀便和呕吐，给予 Solutol 制剂还出现回肠粘液细胞增生。给予 30% Solutol/70% PEG 400（5 mL/kg/d）的狗出现红细胞质量增加和尿液量减少，可能是由于亚临床脱水和血液浓缩。对于 Cremophor 制剂，狗的亚临床胃黏膜下出血的发生率随剂量体积增加，给予 5 mL/kg/d 的狗的血清尿素氮增加。总的来说，无论载体配方或剂量体积如何，两种载体在两种物种中均未产生明显的毒性，但 Solutol 制剂在大鼠中产生的影响较少。一般来说，较低的剂量体积可使严重程度和/或发现的发生率最小化。
