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Functional Coupling of Human Microphysiology Systems: Intestine, Liver, Kidney Proximal Tubule, Blood-Brain Barrier and Skeletal Muscle.

Publication ,  Journal Article
Vernetti, L; Gough, A; Baetz, N; Blutt, S; Broughman, JR; Brown, JA; Foulke-Abel, J; Hasan, N; In, J; Kelly, E; Kovbasnjuk, O; Repper, J ...
Published in: Scientific reports
February 2017

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.

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Published In

Scientific reports

DOI

EISSN

2045-2322

ISSN

2045-2322

Publication Date

February 2017

Volume

7

Start / End Page

42296

Related Subject Headings

  • Terfenadine
  • Organ Specificity
  • Muscle, Skeletal
  • Methylamines
  • Metabolome
  • Liver
  • Kidney Tubules, Proximal
  • Intestines
  • Humans
  • Cholecalciferol
 

Citation

APA
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ICMJE
MLA
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Vernetti, L., Gough, A., Baetz, N., Blutt, S., Broughman, J. R., Brown, J. A., … Taylor, D. L. (2017). Functional Coupling of Human Microphysiology Systems: Intestine, Liver, Kidney Proximal Tubule, Blood-Brain Barrier and Skeletal Muscle. Scientific Reports, 7, 42296. https://doi.org/10.1038/srep42296
Vernetti, Lawrence, Albert Gough, Nicholas Baetz, Sarah Blutt, James R. Broughman, Jacquelyn A. Brown, Jennifer Foulke-Abel, et al. “Functional Coupling of Human Microphysiology Systems: Intestine, Liver, Kidney Proximal Tubule, Blood-Brain Barrier and Skeletal Muscle.Scientific Reports 7 (February 2017): 42296. https://doi.org/10.1038/srep42296.
Vernetti L, Gough A, Baetz N, Blutt S, Broughman JR, Brown JA, et al. Functional Coupling of Human Microphysiology Systems: Intestine, Liver, Kidney Proximal Tubule, Blood-Brain Barrier and Skeletal Muscle. Scientific reports. 2017 Feb;7:42296.
Vernetti, Lawrence, et al. “Functional Coupling of Human Microphysiology Systems: Intestine, Liver, Kidney Proximal Tubule, Blood-Brain Barrier and Skeletal Muscle.Scientific Reports, vol. 7, Feb. 2017, p. 42296. Epmc, doi:10.1038/srep42296.
Vernetti L, Gough A, Baetz N, Blutt S, Broughman JR, Brown JA, Foulke-Abel J, Hasan N, In J, Kelly E, Kovbasnjuk O, Repper J, Senutovitch N, Stabb J, Yeung C, Zachos NC, Donowitz M, Estes M, Himmelfarb J, Truskey G, Wikswo JP, Taylor DL. Functional Coupling of Human Microphysiology Systems: Intestine, Liver, Kidney Proximal Tubule, Blood-Brain Barrier and Skeletal Muscle. Scientific reports. 2017 Feb;7:42296.

Published In

Scientific reports

DOI

EISSN

2045-2322

ISSN

2045-2322

Publication Date

February 2017

Volume

7

Start / End Page

42296

Related Subject Headings

  • Terfenadine
  • Organ Specificity
  • Muscle, Skeletal
  • Methylamines
  • Metabolome
  • Liver
  • Kidney Tubules, Proximal
  • Intestines
  • Humans
  • Cholecalciferol