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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 toxicokinetic data for toxicity studies of repeated administration of 9- [2- (phosphonomethoxy) ethyl] adenine monosodium salt (PMEA-Na). Methods The concentration of drug in the sample was determined by liquid chromatography-mass spectrometry (LC-MS / MS) method. The data were processed by statistical moment method to get the toxicokinetic parameters and to complete the biochemical and histopathological examination. Results AUC appeared to be dose-dependent in single dose and multiple doses of Beagle dog’s vein (14 d, once a day) within the dose range. The AUC were (2.3 ± 0.5), (8.4 ± 1.6), (17.5 ± 3.7) mg · L-1 · h (single dose) and (5.0 ± 5.0) mg · kg-1PMEA-Na at 1.0, 3.0 and 6.0 mg · kg- 0.4), (15.9 ± 3.2), (30.3 ± 4.7) mg · L-1 · h (multiple doses). PMEA-Na was mainly excreted by the kidneys, and renal dysfunction was decreased after 14 days of administration. Compared with the control group, the serum biochemical indexes of 6.0 mg · kg-1 alanine aminotransferase, total bilirubin, urea nitrogen, creatinine and triglyceride were all increased while the glucose level was decreased. Histopathological examination of the 6.0 mg · kg -1 group showed significant pathological changes in the liver and kidney. Conclusion Beagle dogs were given multiple toxicities after intravenous administration of PMEA-Na for 14 days. The toxic target organs were mainly kidney and liver.