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Assessment of Drug Clearance, Metabolite Profile, and Drug Induced Toxicity in a Coculture of Human 3D Liver and Gut Microphysiological Systems: : Toward developing a perfused human liver‐gut interactome
Author(s) -
Sarkar U.,
Tannenbaum S.,
Carrier R.,
Chen K,
Cirit M,
Griffith L.,
Hughes D.,
Large E,
Wishnok J.,
Yu J
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.779.4
Subject(s) - pharmacology , drug metabolism , in vivo , drug , drug development , physiologically based pharmacokinetic modelling , ivivc , metabolite , context (archaeology) , pharmacokinetics , biology , metabolomics , toxicity , drug discovery , computational biology , bioinformatics , medicine , biochemistry , microbiology and biotechnology , paleontology , dissolution testing , biopharmaceutics classification system
Purpose: An early detailed understanding of organ‐specific drug metabolism is crucial in drug discovery and development. Therefore, a robust quantitative high‐throughput preclinical tool for the characterization of organ‐specific metabolites, including reactive species, is important. The aim of this project was to assess drug fate in a human liver and a gut microphysiological systems (MPS) in this context. A UHPLC‐HRMS method for identification of drug metabolites was established using a high mass accuracy, isotope pattern matching, MS/MS‐based scoring algorithm. Accurate masses corresponding to five major Diclofenac (DCF) metabolites from the culture media in liver MPS were observed. PK modeling was used to predict human PK based on drug analysis in the in vivo liver and gut system. Drug clearance in liver, permeability, and apical drug elimination rate in gut were calculated. IVIVC results for DCF agree with available in vivo data on elimination. A metabolomics approach was taken to discover biomarkers of DCF induced toxicity in this system Conclusion Overall, the biology of individual co‐culture liver and gut MPS, including metabolic profiles, drug clearance, and IVIVC data, suggests that the liver‐gut interacting system under development will reflect even more closely potential drug behavior in‐vivo. This two‐organ interactome system would therefore have important potential as a preclinical tool for investigating mechanisms of drug metabolism and toxicity.