Functional Coupling of Human Microphysiology Systems: Intestine, Liver, Kidney Proximal Tubule, Blood-Brain Barrier and Skeletal Muscle.
Organ interactions resulting from drug, metabolite or xenobiotic transport between organs are key components of human metabolism that impact therapeutic action and toxic side effects. Preclinical animal testing often fails to predict adverse outcomes arising from sequential, multi-organ metabolism of drugs and xenobiotics. Human microphysiological systems (MPS) can model these interactions and are predicted to dramatically improve the efficiency of the drug development process. In this study, five human MPS models were evaluated for functional coupling, defined as the determination of organ interactions via an in vivo-like sequential, organ-to-organ transfer of media. MPS models representing the major absorption, metabolism and clearance organs (the jejunum, liver and kidney) were evaluated, along with skeletal muscle and neurovascular models. Three compounds were evaluated for organ-specific processing: terfenadine for pharmacokinetics (PK) and toxicity; trimethylamine (TMA) as a potentially toxic microbiome metabolite; and vitamin D3. We show that the organ-specific processing of these compounds was consistent with clinical data, and discovered that trimethylamine-N-oxide (TMAO) crosses the blood-brain barrier. These studies demonstrate the potential of human MPS for multi-organ toxicity and absorption, distribution, metabolism and excretion (ADME), provide guidance for physically coupling MPS, and offer an approach to coupling MPS with distinct media and perfusion requirements.
University of Pittsburgh, Drug Discovery Institute Pittsburgh, PA, USA.|Department of Computational and Systems Biology, University of Pittsburgh, Baltimore, PA, USA.
Lawrence
L
Vernetti
University of Pittsburgh, Drug Discovery Institute Pittsburgh, PA, USA.|Department of Computational and Systems Biology, University of Pittsburgh, Baltimore, PA, USA.
Albert
A
Gough
Departments of Physiology and Medicine, GI Division, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Nicholas
N
Baetz
Departments of Molecular Virology and Microbiology and Medicine, Baylor College of Medicine, Houston, TX, USA.
Sarah
S
Blutt
Departments of Molecular Virology and Microbiology and Medicine, Baylor College of Medicine, Houston, TX, USA.
James R
JR
Broughman
Department of Physics and Astronomy, Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, Nashville, TN, USA.
Jacquelyn A
JA
Brown
Departments of Physiology and Medicine, GI Division, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Jennifer
J
Foulke-Abel
Departments of Physiology and Medicine, GI Division, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Nesrin
N
Hasan
Departments of Physiology and Medicine, GI Division, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Julie
J
In
Department of Pharmaceutics, University of Washington, WA, USA.
Edward
E
Kelly
Departments of Physiology and Medicine, GI Division, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Olga
O
Kovbasnjuk
Department of Biomedical Engineering, Duke University, Durham, NC, USA.
Jonathan
J
Repper
University of Pittsburgh, Drug Discovery Institute Pittsburgh, PA, USA.
Nina
N
Senutovitch
Departments of Physiology and Medicine, GI Division, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Janet
J
Stabb
Department of Pharmacy, University of Washington, WA, USA.|Kidney Research Institute, University of Washington, WA, USA.
Catherine
C
Yeung
Departments of Physiology and Medicine, GI Division, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Nick C
NC
Zachos
Departments of Physiology and Medicine, GI Division, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Mark
M
Donowitz
Departments of Molecular Virology and Microbiology and Medicine, Baylor College of Medicine, Houston, TX, USA.
Mary
M
Estes
Kidney Research Institute, University of Washington, WA, USA.|Department of Medicine, University of Washington, WA, USA.
Jonathan
J
Himmelfarb
Department of Biomedical Engineering, Duke University, Durham, NC, USA.
George
G
Truskey
Department of Physics and Astronomy, Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, Nashville, TN, USA.|Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.
John P
JP
Wikswo
University of Pittsburgh, Drug Discovery Institute Pittsburgh, PA, USA.|Department of Computational and Systems Biology, University of Pittsburgh, Baltimore, PA, USA.|University of Pittsburgh Cancer Institute, PA, USA.
D Lansing
DL
Taylor
D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000502:physiology*; D002762:Cholecalciferol / Q000378:metabolism; D006801:Humans; D007422:Intestines / Q000502:physiology*; D007687:Kidney Tubules, Proximal / Q000502:physiology*; D008099:Liver / Q000502:physiology*; D055442:Metabolome; D008744:Methylamines / Q000378:metabolism; D018482:Muscle, Skeletal / Q000502:physiology*; D009928:Organ Specificity; D016593:Terfenadine / Q000494:pharmacology
D008744:Methylamines; D002762:Cholecalciferol; D016593:Terfenadine; C023336:trimethylamine