Beagle犬灌胃给予二甲基乙酰胺/聚氧乙烯蓖麻油溶媒28d重复给药毒性研究

A 28-day repeated dose toxicity study of co-solvent Dimethylacetamide/Cremophor EL(DMA/CrEL) in Beagle dogs

目的:通过Beagle犬灌胃(ig)给予二甲基乙酰胺/聚氧乙烯蓖麻油(DMA/CrEL)溶媒的重复给药毒性研究,观察其潜在毒性反应,为临床前安全性评价研究中供试品溶媒的合理选择提供参考依据。方法:将Beagle犬随机分为3组,0.9%Na Cl溶液对照组、溶媒低剂量组(DMA 18.7 mg·kg^(-1),CrEL 10.5 mg·kg^(-1))和溶媒高剂量组(DMA 187.3 mg·kg-1,CrEL 105.0 mg·kg^(-1))。每组10只动物,雌雄各半。ig给药,qd,连续给药28 d,恢复期16 d。分别在检疫期、给药结束以及恢复期的不同时间点进行动物的临床症状、体重、摄食量、心电图、尿液、血液学、血清生化以及组织病理学等各项毒理学指标检测。结果:DMA/CrEL溶媒在低剂量下具有较好的安全性,但高剂量下能够引起动物产生明显毒性反应,包括粪便异常、呕吐、进食量和体重下降、尿液BIL增加,血液RBC,HGB,HCT,PT,APTT增加,血清ALT,AST,ALP,TP,TBIL,γ-GT增加,CHO降低,肝脏重量增加、胸腺重量降低,肝脏、胆囊、肾脏和胸腺等器官的异常组织病理学改变。毒性反应具有一定的可恢复性。结论:在临床前安全性评价中应尽量避免使用大剂量的DMA/CrEL作为供试品溶媒,尤其需要特别注意DMA可能产生的毒性反应,合理选择溶媒给予量。

Objective： To evaluate the potential toxicity of the dimethylacetamide/cremophor EL （DMA/ CrEL） solvent in Beagle dogs following repeated dose gastric tube feeding, and provide evidences for the selection of appropriate solvent in preclinical safety evaluation studies. Methods： Beagle dogs were randomly divided into three groups, including saline control group, solvent low dose group （ DMA 18.7 mg·kg-1 , CrEL 10.5 mg·kg-1） , and high dose group （DMA 187.3 mg·kg-1, CrEL 105.0 mg·kg-1）. Each group contained 10 dogs with female and male in half. All the animals were administered intragastrically with test articles every day continuously for 28 days followed by a 16-day recovery phase. Then a series of toxicologic parameters including clinical signs, body weight, food consumption, electrocardiogram, urinalysis, hematology, serum biochemistry and histopathologic analysis et al were determined during the quarantine period, at the end of dosing, and during the recovery period,respectively. Results： DMA/CrEL solvent of low dose had good safety. However, it caused significant toxicity at high dose, including abnormal feces, vomiting, decrease of food consumption, weight loss, increase of BIL in urine, increase of RBC, HGB, HCT, PT and APTT in peripheral blood, increase of ALT, AST, ALP, TP, TBIL, γ-GT and decrease of CHO in serum, increase of liver weight and decrease of thymus weight, and abnormal histopathologic changes in liver, gallbladder, kidney and thymus et al. The above toxieities were reversible. Conclusion： The use of large doses of DMA/CrEL co-solvent as the vehicle of test articles should be avoided in preclinical safety evaluation studies. Special attention should be paid to DMA toxicity, and selection of appropriate solvent dose.