Lenz E M, Bright J, Knight R, Westwood F R, Davies D, Major H, Wilson I D
Department of Drug Metabolism and Pharmacokinetics, AstraZeneca, Macclesfield, UK.
Biomarkers. 2005 Mar-Jun;10(2-3):173-87. doi: 10.1080/13547500500094034.
The model nephrotoxin gentamicin was administered to male Wistar-derived rats daily, for 7 days, at 60 mg kg-1 day-1, subcutaneously, twice daily. Conventional clinical chemistry urinalysis showed a significant increase in N-acetyl-beta-D-glucosaminidase (NAG) activity from day 3. At necropsy on day 9, clear histological damage to the kidney was noted with all animals showing a generally severe nephropathy primarily focused on the proximal convoluted tubules. The urinary excretion pattern of endogenous metabolites over the time course of the study was studied using a combination of 1H-NMR spectroscopy and HPLC-TOF-MS/MS using electrospray ionization (ESI). Changes in the pattern of endogenous metabolites as a result of daily administration of gentamicin were readily detected by both techniques with significant perturbations of the urinary profile observed from day 7 onwards. The findings by 1H-NMR included raised glucose and reduced trimethylamine N-oxide (TMAO). Changes in metabonomic profiles were observed by HPLC-MS in both positive and negative ESI. The MS data showed reduced xanthurenic acid and kynurenic acid, whilst neutral loss experiments also revealed a changed pattern of sulphate conjugation on gentamicin administration.
将模型肾毒素庆大霉素以60毫克/千克/天的剂量，每天皮下注射两次，连续7天给予雄性Wistar大鼠。常规临床化学尿液分析显示，从第3天起，N-乙酰-β-D-葡萄糖苷酶（NAG）活性显著增加。在第9天尸检时，发现所有动物的肾脏均有明显的组织学损伤，普遍表现为严重的肾病，主要集中在近端曲管。在研究过程中，使用1H-NMR光谱和HPLC-TOF-MS/MS结合电喷雾电离（ESI）技术研究了内源性代谢物的尿排泄模式。两种技术均能轻易检测到由于每日给予庆大霉素而导致的内源性代谢物模式变化，从第7天起观察到尿液谱有显著扰动。1H-NMR的结果包括葡萄糖升高和三甲胺N-氧化物（TMAO）降低。通过HPLC-MS在正ESI和负ESI中均观察到代谢组学谱的变化。质谱数据显示黄尿酸和犬尿酸减少，而中性丢失实验也显示在给予庆大霉素后硫酸盐结合模式发生了变化。
