前药dl-PHPB的急性毒性及伴随毒代动力学研究  

The Research for Acute Toxicity and Toxicokinetics of Potassium 2-(1-Hydroxypentyl)-benzoate by Intravenous Injection in Dogs

作　　者：李江[1] 王爱平[1] 王晓良[1] 徐少锋[1] 李晋[1] 李慧[1] 靳洪涛[1] 

机构地区：[1]中国医学科学院药物研究所,100050

出　　处：《中西医结合心脑血管病杂志》2011年第10期1242-1243,共2页Chinese Journal of Integrative Medicine on Cardio-Cerebrovascular Disease

基　　金：十一五"重大新药创制"(No.2009ZX09102-038;2008ZX09305-001);基本科研业务费(No.2006QN37)专项基金资助

摘　　要：目的评价Beagle犬静脉注射丁基苯酞(dl-NBP)前体2-(α-羟基戊基)苯甲酸钾(dl-PHPB)的急性毒性反应及伴随毒代动力学。方法采用近似致死剂量法(ALD),给药剂量分别为41 mg/kg9、3 mg/kg2、10 mg/kg3、15 mg/kg。同时采用HPLC-UV方法测定血药浓度,使用DAS软件进行数据处理,和毒代动力评价,采血时间为给药后3 min1、5 min3、0 min1、h2、h4、h、6 h和8 h。结果随给药剂量的增加逐渐出现身体颤抖、头部震颤、呕吐、站立不能、后肢肌束震颤等反应,但给药后2 h基本恢复正常;315 mg/kg剂量组动物给药后6 min死亡。dl-PHPB可快速转化为dl-NBP,其AUC0-∞分别为24.8μg hr/mL、49.0μg hr/mL、76.0μg hr/mL,明显低于dl-NBP的AUC0-∞分别为200.8μg hr/mL、340.6μg hr/mL、407.1μg hr/mL。结论 Beagle犬单次静脉注射dl-PHPB的近似致死剂量范围为210 mg/kg^315 mg/kg。伴随毒代动力学研究显示dl-PHPB的毒性反应与其快速转化为dl-NBP密切相关。Objective To study the acute toxicity and toxicokinetics of potassium 2-（1-Hydroxypentyl）-benzoate（dl-PHPB） in beagle dogs.Methods The acute toxicity of dl-PHPB was studied by intravenous injection in 4 Beagle dogs with approximate lethal method（ALD）.The dosages were 41 mg/kg,93 mg/kg,210 mg/kg,315 mg/kg respectively.Blood samples were collected at 3 min,15 min,30 min,1 h,2 h,4 h,6 h,and 8 h after administration and analyzed with validated HPLC-UV method.The data was analyzed by DAS software.Results Following intravenous injection of dl-PHPB at the dose of 41 mg/kg to 210 mg/kg,slight to severe toxicity was showed in beagle dogs：Trembling,head tremors,vomiting,and muscular fasciculation.Then that were returned to normal after 2 h.The dog died at dose of 315 mg/kg.The toxicokinetics of dl-PHPB were performed at the dose of 41 mg/kg to 210 mg/kg.The dl-PHPB AUC0-∞ was 24.8,49.0,and 76.0 μg hr/mL.Cmax was 24.8,49.1,and 76.2 μg/mL.T1/2 was 4.3,5.1,and 4.5 min.Its active metabolite（dl-NBP） AUC0-∞ was 200.8,340.6 and 407.The 1 μg hr/mL,Cmax was 202.3,345.4,and 425.4 μg/mL.T1/2 was 3.8,4.8,and 7.1 min,respectively.Conclusion The acute toxicity results show that the range of approximate lethal dose is 210 mg/kg to 315 mg/kg with single intravenous injection of dl-PHPB in beagle dogs.The toxicokinetics studies show that dl-PHPB was quickly metabolized into dl-NBP,and the toxicity effect of dl-PHPB maybe mainly due to dl-NBP release.

关 键 词：丁基苯酞 2-(α-羟基戊基)苯甲酸钾 毒代动力学 

分 类 号：R743.3[医药卫生—神经病学与精神病学]