Article (Scientific journals)
Modeling the effects of commonly used drugs on human metabolism
Sahoo, Swagatika; Haraldsdottir, Hulda; Fleming, Ronan MT et al.
2014In FEBS Journal
Peer reviewed
 

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Keywords :
Genome scale metabolic network reconstruction; constraint based modeling; reconstruction module; drug metabolism; inborn errors of metabolism
Abstract :
[en] Metabolism contributes significantly to the pharmacokinetics and pharmacodynamics of a drug. In addition, diet and genetics have a profound effect on cellular metabolism under health and disease. Herein, we assembled a comprehensive, literature-based drug metabolic reconstruction of the 18 most highly prescribed drug groups including statins, antihypertensives, immunosuppressants, and analgesics. This reconstruction captures in detail our current understanding of their absorption, intra-cellular distribution, metabolism, and elimination. We combined this drug module with the most comprehensive reconstruction of human metabolism, Recon 2, yielding Recon2_DM1796, which accounts for 2803 metabolites and 8161 reactions. By defining 50 specific drug objectives that captured the overall drug metabolism of these compounds, we investigated effects of dietary composition and inherited metabolic disorders on drug metabolism and drug-drug interactions. Our main findings include (i) shift in dietary patterns significantly affect statins and acetaminophen metabolism, (ii) disturbed statin metabolism contributes to the clinical phenotype of mitochondrial energy disorders, and (iii) the interaction between statins and cyclosporine can be explained by several common metabolic and transport pathways other than the previously established CYP3A4 connection. This work holds the potential for studying adverse drug reactions and designing patient-specific therapies.
Research center :
Luxembourg Centre for Systems Biomedicine (LCSB): Molecular Systems Physiology (Thiele Group)
Luxembourg Centre for Systems Biomedicine (LCSB): Systems Biochemistry (Fleming Group)
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Sahoo, Swagatika ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Haraldsdottir, Hulda ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Fleming, Ronan MT ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Thiele, Ines ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
External co-authors :
no
Language :
English
Title :
Modeling the effects of commonly used drugs on human metabolism
Publication date :
2014
Journal title :
FEBS Journal
ISSN :
1742-464X
Publisher :
Blackwell Publishing, Oxford, United Kingdom
Peer reviewed :
Peer reviewed
Available on ORBilu :
since 14 October 2014

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