前药dl-PHPB在Beagle犬中反复给药毒性及伴随毒代动力学研究

目的评价I类抗脑缺血新药2-（α-羟基戊基）苯甲酸钾（dl-PHPB）在Beagle犬中反复给药30d的毒性及伴随毒代动力学。方法 Beagle犬反复给药30d,给药剂量分别为6、18、54mg/kg（分别相当于临床人体用量的3.6、10.8和32.4倍）并设溶剂对照组,停药后恢复期观察3周。同时采用HPLC-UV方法测定不同剂量下首次和末次给药的血清药物浓度。结果 54mg/kg剂量组的主要毒性反应为部分动物给药过程中出现头部颤抖,给药结束时可见血尿素氮（BUN）、肌酐（Cr）和尿pH值有所增加,相关脏器病理组织学检查未见异常;恢复期结束时上述指标均恢复正常。在6、18、54mg/kg剂量下,药后1h内dl-PHPB即完全转化为丁基苯酞（dl-NBP）。首次给药后,其活性代谢物dl-NBP的AUC0-∞分别为2.8、7.2、32.5μg·h^-1·ml^-1,末次给药dl-NBP的AUC0-∞分别为2.9、8.1、38.7μg·h^-1·ml^-1。其转化为dl-NBP的暴露比（AUC30th/AUC1st）分别为1.02、1.12和1.17。结论 Beagle犬静脉滴注dl-PHPB30d连续给药非毒性反应剂量为18mg/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。

Experimental study on repeated dose toxicity and toxicokinetics of dl-PHPB by intravenous injection in Beagle dogs

Objective To observe the repeated dose toxicity and toxicokinetics of dl-PHPB.Methods The repeated dose toxicity study of dl-PHPB was performed at doses of 6,18,54mg/kg for 30 days（once daily）by intravenous injection in beagle dogs.Parameters evaluated included daily clinical signs,periodic hematology,clinical chemistry,and urinalysis determinations and histopathology examination.On 1st day and 30th day,blood samples were collected at 3min,0.25,0.5,1,2,4,6,24h after administration and analyzed with validated HPLC-UV method,using DAS software to analyze the date.Results In repeated dose toxicity study,at the dose of 54mg/kg showed slight toxicity in beagle dogs：trembling,head tremors,increased BUN and Cr and urine pH etc.There was no toxicologically relevant finding at the end of recovery period.The toxicokinetics of dl-PHPB were performed,and more than 90% of dl-PHPB was converted dl-NBP within 1h.On 1st day,its active metabolite（dl-NBP）AUC0-∞ was 2.8,7.2,32.5μg·h^-1·ml^-1espectively.On 30th day,its active metabolite（dl-NBP）AUC0-∞ was 2.9,8.1,38.7μg·h^-1·ml^-1espectively.There was a slight difference of dl-NBP concentration at the same time point on day 1 and day 30.Conclusion The repeated dose toxicity results show that the no observed adverse effect level is 18mg/kg with intravenous injection of dl-PHPB for 30 days in beagle dogs.The toxicokinetics studies show that dl-PHPB is quickly metabolized into dl-NBP,and the toxicity effect of dl-PHPB maybe mainly due to dl-NBP release.Dl-PHPB has no significantly accumulation effects in beagle dogs after successive intravenous administration.