背景:洛索洛芬氨丁三醇是一种与洛索洛芬相关的新型结构化合物。它已被用于治疗疼痛和炎症。然而,洛索洛芬氨丁三醇的胚胎-胎儿发育毒性(EFDT)尚未在体内进行详细评估.本研究调查了洛索洛芬氨丁三醇在大鼠体内的EFDT和毒代动力学。
方法:这项研究的目的是研究洛索洛芬氨丁三醇(0、1、3和10mg/kg/天)和环磷酰胺钠(CP)(2.8mg/kg/天)对妊娠大鼠在妊娠(GDs)6-15日静脉注射对胚胎胎儿发育的潜在生殖毒性。将妊娠大鼠在GD20上安乐死。活/死胎儿的数量,resorptions,植入,和卢蒂亚,妊娠子宫肿块,胎盘肿块,胎儿性别比例,体重,和骨骼发育进行了评估。在一项伴随的毒物动力学(TK)研究中(每组10只怀孕大鼠),测定血浆TK参数和洛索洛芬氨丁三醇的组织分布。
结果:在GD20时,将大鼠麻醉并剖腹产解剖。外观,内脏,妊娠子宫重量,胚胎植入数,各组母鼠的植入损失率未发现任何病变。在胎儿中,胎儿体重没有显著差异,胚胎吸收数,死胎数量,或胎儿内脏检查在所有试验组与阴性对照组比较。然而,在高剂量组中,与阴性对照组相比,胎儿在骨骼异常方面存在显着差异。TK研究表明,在1-10mg/kg的剂量范围内,首次给药后,洛索洛芬氨丁三醇在动物体内的Cmax和AUC(0-t)与剂量成比例增加,显示线性动力学特征;在最后一次给药后,Cmax和AUC(0-t)与剂量不成比例地增加,表现出非线性动力学特性。组织分布结果表明,洛索洛芬氨丁三醇在孕鼠静脉注射后主要分布在胎盘和肺中;肝脏中的含量随着剂量的增加而降低,心脏中的含量急剧增加;所有组织中的含量均低于血浆中的含量。洛索洛芬氨丁三醇在胎儿组织和器官中主要分布在胎儿肺,肝脏和心脏,含量最低的是羊水。
结论:结论:洛索洛芬氨丁三醇的未观察到的不良反应水平(NOAEL)和最低观察到的不良反应水平(LOAEL)被认为是1和10mg/kg/天,分别。
BACKGROUND: Loxoprofen
tromethamine is a novel structural compound related to loxoprofen. It has been used for the treatment of pain and inflammation. However, the embryo-fetal developmental toxicity (EFDT) of loxoprofen
tromethamine has not been evaluated in detail in vivo. This study investigated the EFDT and toxicokinetics of loxoprofen
tromethamine in rats.
METHODS: The aim of this study was to investigate the potential reproductive toxicity on embryo-fetal development of loxoprofen tromethamine (0, 1, 3, and 10 mg/kg/day) and sodium cyclophosphamide (CP) (2.8 mg/kg/day) administered by intravenous injection to pregnant rats during gestation days (GDs) 6-15. Pregnant rats were euthanized on GD20. The numbers of live/dead fetuses, resorptions, implantations, and corpora lutea, gravid uterus mass, placenta mass, fetal gender ratios, body weight, and skeletal development were evaluated. In a concomitant toxicokinetic (TK) study (10 pregnant rats per group), plasma TK parameters and the tissue distribution of loxoprofen tromethamine were tested.
RESULTS: On GD20, rats were anesthetized and dissected by caesarean section. The appearance, internal organs, gravid uterus weight, embryo implantation number, and implantation loss rate in maternal rats of each group did not reveal any lesions. In fetuses, there were no significant differences in the fetus weight, embryo resorption number, stillbirth number, or fetal visceral examination in all test groups compared to the negative control group. However, in the high-dose group, the fetuses showed significant differences in the anomalies of the bones compared to the negative control group. The TK study showed that in the dose range of 1-10 mg/kg, the Cmax and AUC(0-t) of loxoprofen
tromethamine in animals after the first administration increased proportionally to the dose, showing linear kinetic characteristics; after the last administration, the Cmax and AUC(0-t) increased disproportionately to the dose, showing nonlinear kinetic characteristics. The results of tissue distribution show that loxoprofen tromethamine was mainly distributed in the placenta and lung after the intravenous administration to pregnant rats; the content in the liver was lower and increased sharply in the heart with increasing doses; the content in all tissues was lower than that in the plasma. Loxoprofen
tromethamine in fetal tissues and organs was mainly distributed in fetal lungs, liver and heart, and the lowest content was in amniotic fluid.
CONCLUSIONS: In conclusion, the no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) of loxoprofen tromethamine were considered to be 1 and 10 mg/kg/day, respectively.