Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul 130-650, South Korea.
Anal Chim Acta. 2010 Feb 19;661(1):47-59. doi: 10.1016/j.aca.2009.11.063. Epub 2009 Dec 4.
In order to develop a safety biomarker for atorvastatin, this drug was orally administrated to hyperlipidemic rats, and a metabolomic study was performed. Atorvastatin was given in doses of either 70 mg kg(-1) day(-1) or 250 mg kg(-1) day(-1) for a period of 7 days (n=4 for each group). To evaluate any abnormal effects of the drug, physiological and plasma biochemical parameters were measured and histopathological tests were carried out. Safety biomarkers were derived by comparing these parameters and using both global and targeted metabolic profiling. Global metabolic profiling was performed using liquid chromatography/time of flight/mass spectrometry (LC/TOF/MS) with multivariate data analysis. Several safety biomarker candidates that included various steroids and amino acids were discovered as a result of global metabolic profiling, and they were also confirmed by targeted metabolic profiling using gas chromatography/mass spectrometry (GC/MS) and capillary electrophoresis/mass spectrometry (CE/MS). Serum biochemical and histopathological tests were used to detect abnormal drug reactions in the liver after repeating oral administration of atorvastatin. The metabolic differences between control and the drug-treated groups were compared using PLS-DA score plots. These results were compared with the physiological and plasma biochemical parameters and the results of a histopathological test. Estrone, cortisone, proline, cystine, 3-ureidopropionic acid and histidine were proposed as potential safety biomarkers related with the liver toxicity of atorvastatin. These results indicate that the combined application of global and targeted metabolic profiling could be a useful tool for the discovery of drug safety biomarkers.
为了开发阿托伐他汀的安全生物标志物，将该药物口服给予高脂血症大鼠，并进行代谢组学研究。阿托伐他汀以 70mgkg-1day-1或 250mgkg-1day-1的剂量给药，持续 7 天（每组 4 只）。为了评估药物的任何异常作用，测量了生理和血浆生化参数，并进行了组织病理学测试。通过比较这些参数并使用全局和靶向代谢谱分析，得出了安全生物标志物。使用液相色谱/飞行时间/质谱联用（LC/TOF/MS）和多变量数据分析进行全局代谢谱分析。通过全局代谢谱分析发现了包括各种类固醇和氨基酸在内的几种安全生物标志物候选物，并且通过使用气相色谱/质谱（GC/MS）和毛细管电泳/质谱（CE/MS）的靶向代谢谱分析也得到了证实。通过重复口服给予阿托伐他汀后检测肝脏中的异常药物反应，使用血清生化和组织病理学测试来检测。使用 PLS-DA 得分图比较对照组和药物处理组之间的代谢差异。将这些结果与生理和血浆生化参数以及组织病理学测试的结果进行比较。雌酮、皮质酮、脯氨酸、胱氨酸、3-脲基丙酸和组氨酸被提议为与阿托伐他汀肝毒性相关的潜在安全生物标志物。这些结果表明，全局和靶向代谢谱分析的联合应用可能是发现药物安全生物标志物的有用工具。
