title: Discovery of safety biomarkers for atorvastatin in rat urine using mass spectrometry based metabolomics combined with global and targeted approach.
abstract: 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.
authors.affiliation: Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul 130-650, South Korea.
authors.forename: Bhowmik Salil
authors.initials: BS
authors.lastname: Kumar
authors.forename: Young-Joo
authors.initials: YJ
authors.lastname: Lee
authors.forename: Hong Jae
authors.initials: HJ
authors.lastname: Yi
authors.forename: Bong Chul
authors.initials: BC
authors.lastname: Chung
authors.forename: Byung Hwa
authors.initials: BH
authors.lastname: Jung
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000378:metabolism / Q000652:urine; D000069059:Atorvastatin; D015415:Biomarkers / Q000378:metabolism / Q000652:urine*; D008401:Gas Chromatography-Mass Spectrometry; D006538:Heptanoic Acids / Q000378:metabolism / Q000494:pharmacology / Q000652:urine*; D057230:Limit of Detection; D008297:Male; D055432:Metabolomics; D011758:Pyrroles / Q000378:metabolism / Q000494:pharmacology / Q000652:urine*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012015:Reference Standards
chemical_list: D000924:Anticholesteremic Agents; D015415:Biomarkers; D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin