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ARS Home » Northeast Area » Ithaca, New York » Robert W. Holley Center for Agriculture & Health » Plant, Soil and Nutrition Research » Research » Publications at this Location » Publication #242675
Title: Characterization of a gastrointestinal tract microscale cell culture analog used to predict drug toxicity

Author
item MAHLER, GRETCHEN - Cornell University
item ESCH, MANDY - Cornell University
item Glahn, Raymond
item SHULER, MICHAEL - Cornell University

Submitted to: Biotechnology and Bioengineering
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/17/2009
Publication Date: 9/2/2009
Citation: Mahler, G., Esch, M.B., Glahn, R.P., Shuler, M.L. 2009. Characterization of a gastrointestinal tract microscale cell culture analog used to predict drug toxicity. Biotechnology and Bioengineering. 104(1):193-205.

Interpretive Summary: The lining of the gastrointestinal (GI) tract is the largest surface exposed to the external environment in the human body. One of the main functions of the small intestine is absorption, and intestinal absorption is a route used by essential nutrients, chemicals, and pharmaceuticals to enter the systemic circulation. Understanding the effects of digestion on a drug or chemical, how compounds interact with and are absorbed through the small intestinal epithelium, and how these compounds affect the rest of the body is critical for toxicological evaluation. Our goal is to create physiologically realistic in vitro models of the human GI tract that provide rapid, inexpensive, and accurate predictions of the body’s response to orally delivered drugs and chemicals. Our group has developed an in vitro microscale cell culture analog ('CCA) of the gastrointestinal tract that includes digestion, a mucus layer, and physiologically realistic cell populations. The GI tract 'CCA, coupled with a multi-chamber silicon 'CCA representing the systemic circulation, is described and challenged with acetaminophen. Proof of concept experiments showed that acetaminophen passes through and is metabolized by the in vitro intestinal epithelium and is further metabolized by liver cells, resulting in liver cell toxicity in a dose dependent manner. The 'CCA response is also consistent with in vivo measurements in mice. The system should be broadly useful for studies on orally delivered drugs or ingestion of chemicals with potential toxicity.

Technical Abstract: The lining of the gastrointestinal (GI) tract is the largest surface exposed to the external environment in the human body. One of the main functions of the small intestine is absorption, and intestinal absorption is a route used by essential nutrients, chemicals, and pharmaceuticals to enter the systemic circulation. Understanding the effects of digestion on a drug or chemical, how compounds interact with and are absorbed through the small intestinal epithelium, and how these compounds affect the rest of the body is critical for toxicological evaluation. Our goal is to create physiologically realistic in vitro models of the human GI tract that provide rapid, inexpensive, and accurate predictions of the body’s response to orally delivered drugs and chemicals. Our group has developed an in vitro microscale cell culture analog ('CCA) of the gastrointestinal tract that includes digestion, a mucus layer, and physiologically realistic cell populations. The GI tract 'CCA, coupled with a multi-chamber silicon 'CCA representing the systemic circulation, is described and challenged with acetaminophen. Proof of concept experiments showed that acetaminophen passes through and is metabolized by the in vitro intestinal epithelium and is further metabolized by liver cells, resulting in liver cell toxicity in a dose dependent manner. The 'CCA response is also consistent with in vivo measurements in mice. The system should be broadly useful for studies on orally delivered drugs or ingestion of chemicals with potential toxicity.