Pharmacometabolomic Approach to Predict QT Prolongation in Guinea Pigs

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.

Metabolomic patterns associated to QTc interval in shiftworkers: an explorative analysis

“…As already observed in animal models (Park et al., 2013), this approach might also be useful to identify subjects at risk of developing LQTc also among those under medication, particularly with antipsychotic drugs. Considering the burden of subjects undergoing antipsychotic treatment, public health implications could be relevant.…”

“…Early asymptomatic factors, such as LQTc, are less known. QTc is, in fact, considered as a prognostic factor of arrhythmia, but the physiopathological mechanisms remain still not fully understood (Park et al., 2013 ). Shiftwork is reported as a risk factor for the development of CVD (Frost et al., 2009 ; Murata et al., 1999 , 2005 ).…”

“…To the best of our knowledge, only one report has been published which applied a metabolomic approach to assess metabolic patterns associated with an increase in risk of developing QTc prolongation in Guinea pigs exposed to increasing doses of sparfloxacin, a compound belonging to the third-generation family of Fluoroquinolones, known to induce QTc prolongation (Park et al., 2013 ). No metabolomics studies have been published so far to identify LQTc related metabolic factors in humans.…”

From Metabonomics to Pharmacometabonomics: The Role of Metabolic Profiling in Personalized Medicine

“…These studies contain no predictive or prognostic elements and the literature is becoming confused by the mis-naming of such studies. These recent papers appear to be examples of this phenomenon (Park et al, 2013 ; Wikoff et al, 2013 ; Serrano-Contreras et al, 2016 ).…”

Association of N-Acetyl Asparagine with QTc in Diabetes: A Metabolomics Study

“…In CV disease (CVD), metabolomics has been applied to identify risk factors and understand molecular mechanisms in cardiomyopathies and coronary artery disease (CAD) [ 9 ]. The use of metabolomics to assess the risk of QTc prolongation is currently limited to only two studies in the published literature, which assessed the metabolic profiles in an animal model exposed to a fluroquinolone [ 10 ] and in a small study of patients who were shift workers [ 11 ].…”