9-[2-(膦酰甲氧基)乙基]腺嘌呤一钠盐在比格犬体内的毒代动力学和毒理学研究(英文)

Toxicokinetics and toxicological studies of sodium 9-[2- (phosphonomethoxy) ethyl] adenine in beagle dogs

目的为9-[2-(膦酰甲氧基)乙基]腺嘌呤一钠盐(PMEA-Na)重复给药的毒性研究提供毒代动力学资料。方法采用液相色谱质谱联用方法测定样品中的药物浓度,数据经统计矩方法处理得到毒代动力学参数,并完成血清生化学及组织病理学检测。结果比格(Beagle)犬静脉单次及多次给药(14 d,每日1次)后,在给药剂量范围内, AUC均表现为剂量依赖性。在1.0, 3.0与6.0 mg·kg-1PMEA-Na时,AUC分别为(2.3±0.5),(8.4±1.6),(17.5±3.7)mg·L-1·h(单剂量)和(5.0±0.4),(15.9±3.2),(30.3±4.7) mg·L-1·h(多剂量)。PMEA-Na主要经肾脏排出体外,且给药14 d后肾功能受损药物排泄能力降低。与对照组比较, 6.0 mg·kg-1组血清生化学检测指标丙氨酸氨基转换酶、总胆红素、尿素氮、肌酐及甘油三酯均升高,葡萄糖水平下降。6.0 mg·kg-1组的组织病理学检查发现肝脏和肾脏有明显的病理形态学改变。结论比格犬经静脉多次给PMEA-Na 14 d后出现毒性反应,毒性靶器官主要为肾脏和肝脏。

AIM To provide toxicokinetics data for toxicity studies of repeated doses of sodium 9-[ 2- （ phosphonomethoxy ） ethyl ] adenine （ PMEA-Na ）. METHODS The concentrations of PMEA-Na in plasma and urine were determined by HPLC/MS/MS method after single and multiple iv administrations in dogs. Data were executed by the statistical moment method to acquire the toxicokinetics parameters. Serum biochemical tests and histopathological examination were performed. RESULTS The system exposure of PMEA- Na in dogs was dose-dependent over the dose range of 1.0 -6.0 mg·kg^-1 The areas under the plasma concentration-time curve of PMEA-Na after single and multiple iv administrations at 1.0, 3.0 and 6.0 mg· kg^-1 dosage were （2.3 ±0.5）, （8.4±1.6）, （17.5 ± 3.7） and （5.0±0.4）, （15.9±3.2）, （30.3± 4.7 ） mg· L^- 1· h, respectively. The urinary excretion of PMEA-Na in 72 h after iv administration was （ 87.0 ± 4.8）% at the dose of 3.0mg·kg^-1. In 6.0 mg·kg^-1 dose group, liver enzyme activity of glutamic-pyruvic transaminase and serum levels of total bilirubin, blood urea nitrogen, creatinine and triglycerides were all significantly elevated ; glucose level significantly decreased comparing with the control group. Histopathological observation showed distinct pathological changes in liver and kidney tissues of 6.0 mg · kg^-1 dose group. CONCLUSION There was evidence of toxicity after repeated-dose （ 14 d ） of PMEA-Na in dogs and the major toxicity target organs were the kidney and liver.