摘要
目的:在进行9-[2-(磷酸甲氧基)乙基]腺嘌呤钠(PMEA-Na)SD大鼠慢性毒性研究的同时,研究其伴随毒代动力学及组织分布。方法:采用液相色谱质谱联用方法测定样品中的药物浓度,并进行血清生化学及组织病理学检测。结果:SD大鼠单次及多次iv给药(90 d,每天1次)后,在给药剂量范围内,PMEA-Na在大鼠体内的暴露量与给药剂量呈线性相关。在6,12和24 mg/kg剂量下,AUC分别为7.49,11.63,30.99 mg/L.h(单剂量)和11.43,25.19,54.20 mg/L.h(多剂量)。肾脏中PMEA-Na浓度最高,其次是肝脏和生殖器,且多次给药后其组织浓度升高。血清生化学检测指标AST、CRE、CK及CRE均升高(P<0.01)。组织病理学检查未发现明显的病理形态学改变。结论:PMEA-Na经iv多次给药SD大鼠90 d后有毒性作用及蓄积现象,毒性作用靶器官主要为肾脏、肝脏和生殖器。
Abstract Aim: To study the toxicokinetics of PMEA-Na (mono-sodium salts of 9-[2-(phosphonomethoxy) ethyl] adenine) and its tissues distribution in SD rats during the period of its chronic toxicity study. Method: The concentrations of PMEA-Na in plasma and tissues after single and multiple iv administrations in rats were determined by a sensitive and specific HPLC/MS/MS method. Senma chemistry tests and histopathological examination were also performed. Results:The system exposure of PMEA-Na in body was proven to be linear with dosage over the range of 6 24 mg/kg. The areas under the plasma concentration-time curve (AUC) of PMEA-Na after single and multiple iv administrations at 6, 12 and 24 mg/kg dosage were 7.49, 11.63, 30.99 and 11.43, 25.19, 54.20 mg/L ~ h, respectively. The concentration of PMEA-Na in tissue was increased after repeated-dose, and it was the highest in kidney, followed by liver and genitals after iv administration at 3 mg/kg dosage. Compared to the control group, hver enzyme activities such as AST and CK, senma CRE level were elevated significantly based on senma chemistry tests ( P 〈 0.01 ). But no morphologic changes were observed in histopathological examination. Conclusion:It was evident that toxicity and accumulation occur after multiple (90 d) iv administrations of PMEA-Na in rats. The major toxic target organs of PMEA-Na are the kidney, liver and genitals.
出处
《中国药科大学学报》
CAS
CSCD
北大核心
2006年第4期341-345,共5页
Journal of China Pharmaceutical University
基金
国家高技术研究发展计划("八六三"计划)资助项目(No.2004AA2Z3776)~~