Human Primary Cell-Based Organotypic Microtissues for Modeling Small Intestinal Drug Absorption

Purpose The study evaluates the use of new in vitro primary human cell-based organotypic small intestinal (SMI) microtissues for predicting intestinal drug absorption and drug-drug interaction. Methods The SMI microtissues were reconstructed using human intestinal fibroblasts and enterocytes culture...

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Published inPharmaceutical research Vol. 35; no. 4; pp. 72 - 18
Main Authors Ayehunie, Seyoum, Landry, Tim, Stevens, Zachary, Armento, Alex, Hayden, Patrick, Klausner, Mitchell
Format Journal Article
LanguageEnglish
Published New York Springer US 01.04.2018
Springer
Springer Nature B.V
Subjects
Administration, Oral
Adult
Bioavailability
Biochemistry
Biological Availability
Biomedical and Life Sciences
Biomedical Engineering and Bioengineering
Biomedicine
Caco-2 Cells
Cells
Drug Evaluation, Preclinical - methods
Drug interaction
Drug Interactions
Enterocytes
Enzymes
Epithelial Cells
Female
Fibroblasts
Gastrointestinal agents
Humans
Intestinal Absorption
Intestinal Mucosa - cytology
Intestinal Mucosa - metabolism
Intestine, Small - cytology
Intestine, Small - metabolism
Medical Law
Oral administration
Permeability
Pharmacology/Toxicology
Pharmacy
Physiological aspects
Primary Cell Culture
Research Paper
Small intestine
Tissue Culture Techniques - methods
Young Adult
drug permeation
drug transporters
caco-2
organotypic small intestinal microtissues
drug-drug interaction
drug metabolizing enzymes
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Abstract Purpose The study evaluates the use of new in vitro primary human cell-based organotypic small intestinal (SMI) microtissues for predicting intestinal drug absorption and drug-drug interaction. Methods The SMI microtissues were reconstructed using human intestinal fibroblasts and enterocytes cultured on a permeable support. To evaluate the suitability of the intestinal microtissues to model drug absorption, the permeability coefficients across the microtissues were determined for a panel of 11 benchmark drugs with known human absorption and Caco-2 permeability data. Drug-drug interactions were examined using efflux transporter substrates and inhibitors. Results The 3D–intestinal microtissues recapitulate the structural features and physiological barrier properties of the human small intestine. The microtissues also expressed drug transporters and metabolizing enzymes found on the intestinal wall. Functionally, the SMI microtissues were able to discriminate between low and high permeability drugs and correlated better with human absorption data (r 2  = 0.91) compared to Caco-2 cells (r 2  = 0.71). Finally, the functionality of efflux transporters was confirmed using efflux substrates and inhibitors which resulted in efflux ratios of >2.0 fold and by a decrease in efflux ratios following the addition of inhibitors. Conclusion The SMI microtissues appear to be a useful pre-clinical tool for predicting drug bioavailability of orally administered drugs.
AbstractList Purpose The study evaluates the use of new in vitro primary human cell-based organotypic small intestinal (SMI) microtissues for predicting intestinal drug absorption and drug-drug interaction. Methods The SMI microtissues were reconstructed using human intestinal fibroblasts and enterocytes cultured on a permeable support. To evaluate the suitability of the intestinal microtissues to model drug absorption, the permeability coefficients across the microtissues were determined for a panel of 11 benchmark drugs with known human absorption and Caco-2 permeability data. Drug-drug interactions were examined using efflux transporter substrates and inhibitors. Results The 3D-intestinal microtissues recapitulate the structural features and physiological barrier properties of the human small intestine. The microtissues also expressed drug transporters and metabolizing enzymes found on the intestinal wall. Functionally, the SMI microtissues were able to discriminate between low and high permeability drugs and correlated better with human absorption data (r.sup.2 = 0.91) compared to Caco-2 cells (r.sup.2 = 0.71). Finally, the functionality of efflux transporters was confirmed using efflux substrates and inhibitors which resulted in efflux ratios of >2.0 fold and by a decrease in efflux ratios following the addition of inhibitors. Conclusion The SMI microtissues appear to be a useful pre-clinical tool for predicting drug bioavailability of orally administered drugs.
The study evaluates the use of new in vitro primary human cell-based organotypic small intestinal (SMI) microtissues for predicting intestinal drug absorption and drug-drug interaction. The SMI microtissues were reconstructed using human intestinal fibroblasts and enterocytes cultured on a permeable support. To evaluate the suitability of the intestinal microtissues to model drug absorption, the permeability coefficients across the microtissues were determined for a panel of 11 benchmark drugs with known human absorption and Caco-2 permeability data. Drug-drug interactions were examined using efflux transporter substrates and inhibitors. The 3D-intestinal microtissues recapitulate the structural features and physiological barrier properties of the human small intestine. The microtissues also expressed drug transporters and metabolizing enzymes found on the intestinal wall. Functionally, the SMI microtissues were able to discriminate between low and high permeability drugs and correlated better with human absorption data (r.sup.2 = 0.91) compared to Caco-2 cells (r.sup.2 = 0.71). Finally, the functionality of efflux transporters was confirmed using efflux substrates and inhibitors which resulted in efflux ratios of >2.0 fold and by a decrease in efflux ratios following the addition of inhibitors. The SMI microtissues appear to be a useful pre-clinical tool for predicting drug bioavailability of orally administered drugs.
PurposeThe study evaluates the use of new in vitro primary human cell-based organotypic small intestinal (SMI) microtissues for predicting intestinal drug absorption and drug-drug interaction.MethodsThe SMI microtissues were reconstructed using human intestinal fibroblasts and enterocytes cultured on a permeable support. To evaluate the suitability of the intestinal microtissues to model drug absorption, the permeability coefficients across the microtissues were determined for a panel of 11 benchmark drugs with known human absorption and Caco-2 permeability data. Drug-drug interactions were examined using efflux transporter substrates and inhibitors.ResultsThe 3D–intestinal microtissues recapitulate the structural features and physiological barrier properties of the human small intestine. The microtissues also expressed drug transporters and metabolizing enzymes found on the intestinal wall. Functionally, the SMI microtissues were able to discriminate between low and high permeability drugs and correlated better with human absorption data (r2 = 0.91) compared to Caco-2 cells (r2 = 0.71). Finally, the functionality of efflux transporters was confirmed using efflux substrates and inhibitors which resulted in efflux ratios of >2.0 fold and by a decrease in efflux ratios following the addition of inhibitors.ConclusionThe SMI microtissues appear to be a useful pre-clinical tool for predicting drug bioavailability of orally administered drugs.
The study evaluates the use of new in vitro primary human cell-based organotypic small intestinal (SMI) microtissues for predicting intestinal drug absorption and drug-drug interaction.PURPOSEThe study evaluates the use of new in vitro primary human cell-based organotypic small intestinal (SMI) microtissues for predicting intestinal drug absorption and drug-drug interaction.The SMI microtissues were reconstructed using human intestinal fibroblasts and enterocytes cultured on a permeable support. To evaluate the suitability of the intestinal microtissues to model drug absorption, the permeability coefficients across the microtissues were determined for a panel of 11 benchmark drugs with known human absorption and Caco-2 permeability data. Drug-drug interactions were examined using efflux transporter substrates and inhibitors.METHODSThe SMI microtissues were reconstructed using human intestinal fibroblasts and enterocytes cultured on a permeable support. To evaluate the suitability of the intestinal microtissues to model drug absorption, the permeability coefficients across the microtissues were determined for a panel of 11 benchmark drugs with known human absorption and Caco-2 permeability data. Drug-drug interactions were examined using efflux transporter substrates and inhibitors.The 3D-intestinal microtissues recapitulate the structural features and physiological barrier properties of the human small intestine. The microtissues also expressed drug transporters and metabolizing enzymes found on the intestinal wall. Functionally, the SMI microtissues were able to discriminate between low and high permeability drugs and correlated better with human absorption data (r2 = 0.91) compared to Caco-2 cells (r2 = 0.71). Finally, the functionality of efflux transporters was confirmed using efflux substrates and inhibitors which resulted in efflux ratios of >2.0 fold and by a decrease in efflux ratios following the addition of inhibitors.RESULTSThe 3D-intestinal microtissues recapitulate the structural features and physiological barrier properties of the human small intestine. The microtissues also expressed drug transporters and metabolizing enzymes found on the intestinal wall. Functionally, the SMI microtissues were able to discriminate between low and high permeability drugs and correlated better with human absorption data (r2 = 0.91) compared to Caco-2 cells (r2 = 0.71). Finally, the functionality of efflux transporters was confirmed using efflux substrates and inhibitors which resulted in efflux ratios of >2.0 fold and by a decrease in efflux ratios following the addition of inhibitors.The SMI microtissues appear to be a useful pre-clinical tool for predicting drug bioavailability of orally administered drugs.CONCLUSIONThe SMI microtissues appear to be a useful pre-clinical tool for predicting drug bioavailability of orally administered drugs.
The study evaluates the use of new in vitro primary human cell-based organotypic small intestinal (SMI) microtissues for predicting intestinal drug absorption and drug-drug interaction. The SMI microtissues were reconstructed using human intestinal fibroblasts and enterocytes cultured on a permeable support. To evaluate the suitability of the intestinal microtissues to model drug absorption, the permeability coefficients across the microtissues were determined for a panel of 11 benchmark drugs with known human absorption and Caco-2 permeability data. Drug-drug interactions were examined using efflux transporter substrates and inhibitors. The 3D-intestinal microtissues recapitulate the structural features and physiological barrier properties of the human small intestine. The microtissues also expressed drug transporters and metabolizing enzymes found on the intestinal wall. Functionally, the SMI microtissues were able to discriminate between low and high permeability drugs and correlated better with human absorption data (r  = 0.91) compared to Caco-2 cells (r  = 0.71). Finally, the functionality of efflux transporters was confirmed using efflux substrates and inhibitors which resulted in efflux ratios of >2.0 fold and by a decrease in efflux ratios following the addition of inhibitors. The SMI microtissues appear to be a useful pre-clinical tool for predicting drug bioavailability of orally administered drugs.
Purpose The study evaluates the use of new in vitro primary human cell-based organotypic small intestinal (SMI) microtissues for predicting intestinal drug absorption and drug-drug interaction. Methods The SMI microtissues were reconstructed using human intestinal fibroblasts and enterocytes cultured on a permeable support. To evaluate the suitability of the intestinal microtissues to model drug absorption, the permeability coefficients across the microtissues were determined for a panel of 11 benchmark drugs with known human absorption and Caco-2 permeability data. Drug-drug interactions were examined using efflux transporter substrates and inhibitors. Results The 3D–intestinal microtissues recapitulate the structural features and physiological barrier properties of the human small intestine. The microtissues also expressed drug transporters and metabolizing enzymes found on the intestinal wall. Functionally, the SMI microtissues were able to discriminate between low and high permeability drugs and correlated better with human absorption data (r 2  = 0.91) compared to Caco-2 cells (r 2  = 0.71). Finally, the functionality of efflux transporters was confirmed using efflux substrates and inhibitors which resulted in efflux ratios of >2.0 fold and by a decrease in efflux ratios following the addition of inhibitors. Conclusion The SMI microtissues appear to be a useful pre-clinical tool for predicting drug bioavailability of orally administered drugs.
ArticleNumber 72
Audience Academic
Author Landry, Tim
Stevens, Zachary
Klausner, Mitchell
Hayden, Patrick
Ayehunie, Seyoum
Armento, Alex
AuthorAffiliation 1 MatTek Corporation, 200 Homer Avenue, Ashland, Massachusetts, USA
AuthorAffiliation_xml – name: 1 MatTek Corporation, 200 Homer Avenue, Ashland, Massachusetts, USA
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  givenname: Seyoum
  orcidid: 0000-0002-4365-5504
  surname: Ayehunie
  fullname: Ayehunie, Seyoum
  email: sayehunie@mattek.com
  organization: MatTek Corporation
– sequence: 2
  givenname: Tim
  surname: Landry
  fullname: Landry, Tim
  organization: MatTek Corporation
– sequence: 3
  givenname: Zachary
  surname: Stevens
  fullname: Stevens, Zachary
  organization: MatTek Corporation
– sequence: 4
  givenname: Alex
  surname: Armento
  fullname: Armento, Alex
  organization: MatTek Corporation
– sequence: 5
  givenname: Patrick
  surname: Hayden
  fullname: Hayden, Patrick
  organization: MatTek Corporation
– sequence: 6
  givenname: Mitchell
  surname: Klausner
  fullname: Klausner, Mitchell
  organization: MatTek Corporation
BackLink https://www.ncbi.nlm.nih.gov/pubmed/29476278$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
Copyright Springer Science+Business Media, LLC, part of Springer Nature 2018
COPYRIGHT 2018 Springer
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Issue 4
Keywords drug permeation
drug transporters
caco-2
organotypic small intestinal microtissues
drug-drug interaction
drug metabolizing enzymes
Language English
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Snippet Purpose The study evaluates the use of new in vitro primary human cell-based organotypic small intestinal (SMI) microtissues for predicting intestinal drug...
The study evaluates the use of new in vitro primary human cell-based organotypic small intestinal (SMI) microtissues for predicting intestinal drug absorption...
Purpose The study evaluates the use of new in vitro primary human cell-based organotypic small intestinal (SMI) microtissues for predicting intestinal drug...
PurposeThe study evaluates the use of new in vitro primary human cell-based organotypic small intestinal (SMI) microtissues for predicting intestinal drug...
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SubjectTerms Administration, Oral
Adult
Bioavailability
Biochemistry
Biological Availability
Biomedical and Life Sciences
Biomedical Engineering and Bioengineering
Biomedicine
Caco-2 Cells
Cells
Drug Evaluation, Preclinical - methods
Drug interaction
Drug Interactions
Enterocytes
Enzymes
Epithelial Cells
Female
Fibroblasts
Gastrointestinal agents
Humans
Intestinal Absorption
Intestinal Mucosa - cytology
Intestinal Mucosa - metabolism
Intestine, Small - cytology
Intestine, Small - metabolism
Medical Law
Oral administration
Permeability
Pharmacology/Toxicology
Pharmacy
Physiological aspects
Primary Cell Culture
Research Paper
Small intestine
Tissue Culture Techniques - methods
Young Adult
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Title Human Primary Cell-Based Organotypic Microtissues for Modeling Small Intestinal Drug Absorption
URI https://link.springer.com/article/10.1007/s11095-018-2362-0
https://www.ncbi.nlm.nih.gov/pubmed/29476278
https://www.proquest.com/docview/2007683749
https://www.proquest.com/docview/2007980791
https://pubmed.ncbi.nlm.nih.gov/PMC6599640
Volume 35
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