Pharmacometabolomic Approach to Predict QT Prolongation in Guinea Pigs

Title
Pharmacometabolomic Approach to Predict QT Prolongation in Guinea Pigs
Author(s)
강원구박정현[박정현]노금한이해원[이해원]임미선성숙진[성숙진]서정주[서정주]김은정[김은정]윤영란[윤영란]
Keywords
SUDDEN CARDIAC DEATH; TORSADES-DE-POINTES; NUCLEAR-MAGNETIC-RESONANCE; FLUOROQUINOLONE ANTIBACTERIAL AGENTS; CORONARY-HEART-DISEASE; MASS-SPECTROMETRY; LIQUID-CHROMATOGRAPHY; METABOLIC SYNDROME; BLOOD-PRESSURE; CARDIOVASCULAR-DISEASE
Issue Date
201304
Publisher
PUBLIC LIBRARY SCIENCE
Citation
PLOS ONE, v.8, no.4
Abstract
Drug-induced torsades de pointes (TdP), a life-threatening arrhythmia associated with prolongation of the QT interval, has been a significant reason for withdrawal of several medicines from the market. Prolongation of the QT interval is considered as the best biomarker for predicting the torsadogenic risk of a new chemical entity. Because of the difficulty assessing the risk for TdP during drug development, we evaluated the metabolic phenotype for predicting QT prolongation induced by sparfloxacin, and elucidated the metabolic pathway related to the QT prolongation. We performed electrocardiography analysis and liquid chromatography-mass spectroscopy-based metabolic profiling of plasma samples obtained from 15 guinea pigs after administration of sparfloxacin at doses of 33.3, 100, and 300 mg/kg. Principal component analysis and partial least squares modelling were conducted to select the metabolites that substantially contributed to the prediction of QT prolongation. QTc increased significantly with increasing dose (r = 0.93). From the PLS analysis, the key metabolites that showed the highest variable importance in the projection values (>1.5) were selected, identified, and used to determine the metabolic network. In particular, cytidine-5'-diphosphate (CDP), deoxycorticosterone, L-aspartic acid and stearic acid were found to be final metabolomic phenotypes for the prediction of QT prolongation. Metabolomic phenotypes for predicting drug-induced QT prolongation of sparfloxacin were developed and can be applied to cardiac toxicity screening of other drugs. In addition, this integrative pharmacometabolomic approach would serve as a good tool for predicting pharmacodynamic or toxicological effects caused by changes in dose.
URI
http://hdl.handle.net/YU.REPOSITORY/26083http://dx.doi.org/10.1371/journal.pone.0060556
ISSN
1932-6203
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약학대학 > 약학부 > Articles
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