中和抗体对促黄体激素释放激素-绿脓杆菌外毒素A暴露水平的影响

目的研究恒河猴注射促黄体激素释放激素-绿脓杆菌外毒素A(GP38)后体内中和抗体的产生及其对药物暴露水平的影响。方法恒河猴24只随机分成4组(即对照组、低、中、高剂量组),每组6只,♀♂各半,分别给予生理盐水、50、100、300μg.kg-1GP38;采用ELISA法测定GP38及抗体滴度,中和抗体的测定采用IC50法间接测定。结果恒河猴给药2 wk后产生抗体,具有中和GP38活性的作用;GP38首次静脉注射50、100、300μg.kg-1时,毒代动力学参数Cmax分别为(866±88)、(1466±113)、(5436±733)μg.L-1,AUC0-t分别为(322±33)、(587±93)、(2201±307)μg.h.L-1,MRT分别为(0.27±0.02)、(0.31±0.02)、(0.40±0.08)h;相同剂量反复给药,第7次(d 14)给药后的毒代动力学参数Cmax分别为(352±136)、(589±372)、(1013±642)μg.L-1,AUC0-t分别为(139±55、322±222)、(962±743)μg.h.L-1,MRT分别为(0.26±0.03)、(0.39±0.08)、(0.68±0.45)h;试验动物毒性反应在给药1～3 wk较严重,之后毒性反应逐渐减弱。结论恒河猴反复静脉注射GP38,能够产生中和抗体,降低药物的体内暴露水平。

Effects of neutralizing antibody on exposure to GP38 in rhesus monkeys

Aim To investigate the effects of grown releasing hormone-pseudomonas aeruginosa exotoxin 38(GP38) neutralizing antibody on drug exposure in rhesus monkeys.Methods A total of 24 rhesus monkeys were randomly divided into 4 groups.Three groups were administrated 50,100,and 300 μg·kg-1 GP38 every other day for 12 weeks,respectively.An iv sodium chloride physiological solution group was served as control.An ELISA method was used to determine the GP38 concentration and its antibody.Neutralizing antibodies expressed as IC50 of GP38 cytotoxicity.Results Neutralizing antibodies enhanced clearance of GP38 from the circulation.The toxicokinetic parameters of GP38 for the three dose on day 1 were Cmax:(866±88),(1466±113),(5436±733) μg·L-1,AUC0-t:(322 ± 33),(587±93),(2201±307) μg·h·L-1,MRT:(0.27±0.02),(0.31±0.02),(0.40±0.08) h,on day 14 were Cmax:(352±136),(589±372),(1013±642) μg·L-1,AUC0-t:(139±55),(322±222),(962±743) μg·h·L-1,MRT:(0.26±0.03),(0.39±0.08),(0.68±0.45) h,respectively.The animals that received 300 μg·kg-1 GP38 experienced severe,life-threatened toxicity during 1~3 weeks.Conclusion This study demonstrates that neutralizing antibody causes a significant reduction of exposure levels of GP38 in rhesus monkeys.