Drug Safety Assessment, Biologie Servier, Gidy, France.
Regul Toxicol Pharmacol. 2010 Jul-Aug;57(2-3):284-90. doi: 10.1016/j.yrtph.2010.03.008. Epub 2010 Mar 27.
Drug safety research is frequently faced with the challenge of the selection of appropriate vehicles for use in in vivo non-clinical safety assessment studies. Reported here are the results of blend Labrasol, Labrafil and Transcutol, [L/L/T, (4/4/2, v/v/v)], excipients used as bioavailability enhancer and solubilizer for poorly water-soluble compounds and tested daily for 4 weeks by oral route in Wistar rats (10/sex/group) at dose volumes of 5, 10 or 20 mL/kg/day and compared to controls given 20 mL/kg/day of 1% (w/v) hydroxyethylcellulose in purified water. L/L/T was broadly well tolerated at 5 mL/kg/day and lethal at 20 mL/kg/day in 1 of 20 rats treated at this level. Changes in appearance and behaviour were observed from 10 mL/kg/day with volume-related incidence, severity and duration. Reduced feed intake observed from 5 (females) or 10 mL/kg/day (males) resulted in low bodyweights for high volume males only (-11% of controls). There was a volume-related induction of hepatic CYP 1A1/2, 2B1/2 and/or 2E1 subfamilies from 5 mL/kg/day, with high liver weight, centrilobular hepatocellular hypertrophy and high ALT, triglyceride and cholesterol serum values at 20 mL/kg/day. Renal tubular dilation in medulla, cortical cell degeneration/necrosis with granular material in adjacent glomerular spaces, crystal deposits in the inner medulla, papilla and/or renal pelvis, and tubular mineralization, associated with proteinuria and calcium oxalate crystalluria, were observed at 20 mL/kg/day as well as vacuolation in the adrenal cortex, with a sex-dependant localization. According to these results, 5 mL/kg/day was considered as an acceptable volume for further use of L/L/T (4/4/2, v/v/v) blend as a vehicle for poorly water soluble drugs in Wistar rat toxicity studies.
药物安全性研究经常面临选择合适载体用于体内非临床安全性评估研究的挑战。本文报告了混合 Labrasol、Labrafil 和 Transcutol（L/L/T，（4/4/2，v/v/v））的结果，这些辅料被用作生物利用度增强剂和难溶性化合物的增溶剂，以每天口服途径给予 Wistar 大鼠（每组 10 只，雌雄各半），剂量体积为 5、10 或 20 mL/kg/天，并与每天给予 20 mL/kg/天的 1%（w/v）羟乙基纤维素在纯化水中的对照组进行比较。L/L/T 在 5 mL/kg/天的剂量下广泛耐受良好，在 20 mL/kg/天的剂量下有 1 只大鼠（20 只中的 1 只）死亡。从 10 mL/kg/天开始，外观和行为发生变化，与体积相关的发生率、严重程度和持续时间。从 5（雌性）或 10 mL/kg/天（雄性）开始观察到采食量减少，导致高体积雄性体重降低（比对照组低 11%）。从 5 mL/kg/天开始，与体积相关的 CYP 1A1/2、2B1/2 和/或 2E1 亚家族诱导，20 mL/kg/天时肝重增加、中央小叶肝细胞肥大和 ALT、甘油三酯和胆固醇血清值升高。20 mL/kg/天观察到髓质肾小管扩张、皮质细胞变性/坏死伴相邻肾小球空间内颗粒物质、内髓、乳头和/或肾盂内晶体沉积以及管状矿化，伴有蛋白尿和草酸钙结晶尿，以及肾上腺皮质空泡化，具有性别依赖性定位。根据这些结果，5 mL/kg/天被认为是进一步使用 L/L/T（4/4/2，v/v/v）混合物作为 Wistar 大鼠毒性研究中难溶性药物载体的可接受体积。
