NDLI: Pharmacometabolomic Approach to Predict QT Prolongation in Guinea Pigs

Content Provider	PubMed Central
Author	Park, Jeonghyeon Noh, Keumhan Lee, Hae Won Lim, Mi-sun Seong, Sook Jin Seo, Jeong Ju Kim, Eun-jung Kang, Wonku Yoon, Young-ran
Editor	Karakousis, Petros C.
Copyright Year	2013
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.
Related Links	http://dx.doi.org/10.1371/journal.pone.0060556
Starting Page	60556
File Format	PDF
ISSN	19326203
e-ISSN	19326203
Journal	PLoS ONE
Issue Number	4
Volume Number	8
Language	English
Publisher	Public Library of Science
Publisher Date	2013-04-01
Access Restriction	Open
Rights Holder	Public Library of Science
Subject Keyword	Biochemistry, Genetics and Molecular Biology(all) Agricultural and Biological Sciences(all) Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

Randomized, Controlled, Thorough QT/QTc Study Shows Absence of QT Prolongation with Luseogliflozin in Healthy Japanese Subjects

Heart Rate-Corrected QT Interval Helps Predict Mortality after Intentional Organophosphate Poisoning

Pharmacometabolomic Signature of Ataxia SCA1 Mouse Model and Lithium Effects

Vaccination with Recombinant Mycobacterium tuberculosis PknD Attenuates Bacterial Dissemination to the Brain in Guinea Pigs

Non-Diabetic Hyperglycemia Exacerbates Disease Severity in Mycobacterium tuberculosis Infected Guinea Pigs

A Network Approach to Predict Pathogenic Genes for Fusarium graminearum

Evidence for Oxidative Stress and Defective Antioxidant Response in Guinea Pigs with Tuberculosis

ESAT-6/CFP10 Skin Test Predicts Disease in M. tuberculosis-Infected Guinea Pigs

Ribbon Synapse Plasticity in the Cochleae of Guinea Pigs after Noise-Induced Silent Damage

Pharmacometabolomic Approach to Predict QT Prolongation in Guinea Pigs

Similar Documents

Randomized, Controlled, Thorough QT/QTc Study Shows Absence of QT Prolongation with Luseogliflozin in Healthy Japanese Subjects

Heart Rate-Corrected QT Interval Helps Predict Mortality after Intentional Organophosphate Poisoning

Pharmacometabolomic Signature of Ataxia SCA1 Mouse Model and Lithium Effects

Vaccination with Recombinant Mycobacterium tuberculosis PknD Attenuates Bacterial Dissemination to the Brain in Guinea Pigs

Non-Diabetic Hyperglycemia Exacerbates Disease Severity in Mycobacterium tuberculosis Infected Guinea Pigs

A Network Approach to Predict Pathogenic Genes for Fusarium graminearum

Evidence for Oxidative Stress and Defective Antioxidant Response in Guinea Pigs with Tuberculosis

ESAT-6/CFP10 Skin Test Predicts Disease in M. tuberculosis-Infected Guinea Pigs

Ribbon Synapse Plasticity in the Cochleae of Guinea Pigs after Noise-Induced Silent Damage

Pharmacometabolomic Approach to Predict QT Prolongation in Guinea Pigs