|MCAULIFFE, GRETCHEN - Cornell University - New York|
|CHANG, JUNG YUN - Korea Food And Drug Administration|
|SHULER, MICHAEL - Cornell University - New York|
Submitted to: Molecular and Cellular Biomechanics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/20/2008
Publication Date: 9/1/2008
Citation: Mcauliffe, G.J., Chang, J., Glahn, R.P., Shuler, M.L. 2008. Development of a gastrointestinal tract microscale cell culture analog to predict drug transport. Molecular and Cellular Biomechanics. 5(2):119-132.
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 bodys response to orally delivered drugs and chemicals. Our group has developed an in vitro microscale cell culture analog (uCCA) of the GI tract that includes digestion, a mucus layer, and physiologically realistic cell populations. The GI tract uCCA, coupled with a multichamber silicon uCCA 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 uCCA 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: Microscale cell culture analogs (uCCAs) are used to study the metabolism and toxicity of a chemical or drug. These in vitro devices are physical replicas of physiologically based pharmacokinetic models that combine microfabrication and cell culture. The goal of this project is to add an independent GI tract uCCA to a multi-chamber chip uCCA representing the primary circulation. The GI tract uCCA consists of two chambers separated by a microporous membrane on which intestinal epithelial cells are cultured. Compounds of interest are pumped through the top chamber, allowing the drug to be absorbed through the epithelial layer and circulated into the chip uCCA. The chip and GI tract uCCAs have been used to recreate the toxic effects of acetaminophen. Preliminary results have shown that the GI tract uCCA acts as a barrier to drugs entering the chip, mimicking in vivo function in this regard.