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Title: Translational systems pharmacology-based predictive assessment of drug-induced cardiomyopathy: Predictive Assessment of Drug-Induced Cardiomyopathy

Authors:
 [1];  [1];  [2];  [3];  [4];  [1]
  1. Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring Maryland USA
  2. Department of Biomedical Sciences, University of North Dakota, School of Medicine & Health Sciences, Grand Forks North Dakota USA
  3. College of Pharmacy, University of Michigan, Ann Arbor Michigan USA
  4. School of Mechanical Engineering, National Technical University of Athens, Zografou Greece
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1417211
Resource Type:
Journal Article: Published Article
Journal Name:
CPT: Pharmacometrics & Systems Pharmacology
Additional Journal Information:
Related Information: CHORUS Timestamp: 2018-01-17 03:19:45; Journal ID: ISSN 2163-8306
Publisher:
Wiley Blackwell (John Wiley & Sons)
Country of Publication:
Country unknown/Code not available
Language:
English

Citation Formats

Messinis, Dimitris E., Melas, Ioannis N., Hur, Junguk, Varshney, Navya, Alexopoulos, Leonidas G., and Bai, Jane P. F. Translational systems pharmacology-based predictive assessment of drug-induced cardiomyopathy: Predictive Assessment of Drug-Induced Cardiomyopathy. Country unknown/Code not available: N. p., 2018. Web. doi:10.1002/psp4.12272.
Messinis, Dimitris E., Melas, Ioannis N., Hur, Junguk, Varshney, Navya, Alexopoulos, Leonidas G., & Bai, Jane P. F. Translational systems pharmacology-based predictive assessment of drug-induced cardiomyopathy: Predictive Assessment of Drug-Induced Cardiomyopathy. Country unknown/Code not available. doi:10.1002/psp4.12272.
Messinis, Dimitris E., Melas, Ioannis N., Hur, Junguk, Varshney, Navya, Alexopoulos, Leonidas G., and Bai, Jane P. F. 2018. "Translational systems pharmacology-based predictive assessment of drug-induced cardiomyopathy: Predictive Assessment of Drug-Induced Cardiomyopathy". Country unknown/Code not available. doi:10.1002/psp4.12272.
@article{osti_1417211,
title = {Translational systems pharmacology-based predictive assessment of drug-induced cardiomyopathy: Predictive Assessment of Drug-Induced Cardiomyopathy},
author = {Messinis, Dimitris E. and Melas, Ioannis N. and Hur, Junguk and Varshney, Navya and Alexopoulos, Leonidas G. and Bai, Jane P. F.},
abstractNote = {},
doi = {10.1002/psp4.12272},
journal = {CPT: Pharmacometrics & Systems Pharmacology},
number = ,
volume = ,
place = {Country unknown/Code not available},
year = 2018,
month = 1
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at 10.1002/psp4.12272

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  • Early detection of drug-induced cholestasis remains a challenge during drug development. We have developed and validated a biorelevant sandwich-cultured hepatocytes- (SCH) based model that can identify compounds causing cholestasis by altering bile acid disposition. Human and rat SCH were exposed (24–48 h) to known cholestatic and/or hepatotoxic compounds, in the presence or in the absence of a concentrated mixture of bile acids (BAs). Urea assay was used to assess (compromised) hepatocyte functionality at the end of the incubations. The cholestatic potential of the compounds was expressed by calculating a drug-induced cholestasis index (DICI), reflecting the relative residual urea formation bymore » hepatocytes co-incubated with BAs and test compound as compared to hepatocytes treated with test compound alone. Compounds with clinical reports of cholestasis, including cyclosporin A, troglitazone, chlorpromazine, bosentan, ticlopidine, ritonavir, and midecamycin showed enhanced toxicity in the presence of BAs (DICI ≤ 0.8) for at least one of the tested concentrations. In contrast, the in vitro toxicity of compounds causing hepatotoxicity by other mechanisms (including diclofenac, valproic acid, amiodarone and acetaminophen), remained unchanged in the presence of BAs. A safety margin (SM) for drug-induced cholestasis was calculated as the ratio of lowest in vitro concentration for which was DICI ≤ 0.8, to the reported mean peak therapeutic plasma concentration. SM values obtained in human SCH correlated well with reported % incidence of clinical drug-induced cholestasis, while no correlation was observed in rat SCH. This in vitro model enables early identification of drug candidates causing cholestasis by disturbed BA handling. - Highlights: • Novel in vitro assay to detect drug-induced cholestasis • Rat and human sandwich-cultured hepatocytes (SCH) as in vitro models • Cholestatic compounds sensitize SCH to toxic effects of accumulating bile acids • Drug-induced cholestasis index (DICI) as measure of a drug's cholestatic signature • In vitro findings correlate well with clinical reports on cholestasis.« less
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