An on-chip small intestine-liver model for pharmacokinetic studies.
Testing of drug effects and cytotoxicity by using cultured cells has been widely performed as an alternative to animal testing. However, the estimation of pharmacokinetics by conventional cell-based assay methods is difficult because of the inability to evaluate multiorgan effects. An important challenge in the field is to mimic the organ-to-organ network in the human body by using a microfluidic network connecting small-scale tissues based on recently emerging MicroTAS (Micro Total Analysis Systems) technology for prediction of pharmacokinetics. Here, we describe an on-chip small intestine-liver coupled model for pharmacokinetic studies. To construct an in vitro pharmacokinetic model that appropriately models in vivo conditions, physiological parameters such as the structure of internal circulation, volume ratios of each organ, and blood flow ratio of the portal vein to the hepatic artery were mimicked using microfluidic networks. To demonstrate interactions between organs in vitro in pharmacokinetic studies, Caco-2, HepG2, and A549 cell cultures were used as organ models of the small intestine, liver, and lung, respectively, and connected to each other through a microporous membrane and microchannels to prepare a simple model of a physiological organ-to-organ network. The on-chip organ model assay using three types of substrate-epirubicine (EPI), irinotecan (CPT-11), and cyclophosphamide (CPA)-were conducted to model the effects of orally administered or biologically active anticancer drugs. The result suggested that the device can replicate physiological phenomena such as activity of the anticancer drugs on the target cells. This microfluidic device can thus be used as an in vitro organ model to predict the pharmacokinetics of drugs in the human body and may thus provide not only an alternative to animal testing but also a method of obtaining parameters for in silico models of physiologically based pharmacokinetics.
Institute of Industrial Science, the University of Tokyo, Tokyo, Japan Department of Mechanical Engineering, Tokai University, Kanagawa, Japan Core Research for Evolutionary Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan.
Hiroshi
H
Kimura
Institute of Industrial Science, the University of Tokyo, Tokyo, Japan.
Takashi
T
Ikeda
Institute of Industrial Science, the University of Tokyo, Tokyo, Japan.
Hidenari
H
Nakayama
Institute of Industrial Science, the University of Tokyo, Tokyo, Japan Core Research for Evolutionary Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan.
Yasuyuki
Y
Sakai
Institute of Industrial Science, the University of Tokyo, Tokyo, Japan Core Research for Evolutionary Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan tfujii@iis.u-tokyo.ac.jp.
Teruo
T
Fujii
D000818:Animals; D018938:Caco-2 Cells; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D003198:Computer Simulation; D003520:Cyclophosphamide / Q000493:pharmacokinetics*; D004354:Drug Screening Assays, Antitumor; D015251:Epirubicin / Q000493:pharmacokinetics*; D056945:Hep G2 Cells; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects / Q000502:physiology*; D000077146:Irinotecan; D056656:Lab-On-A-Chip Devices / Q000706:statistics & numerical data*; D008099:Liver / Q000187:drug effects / Q000502:physiology*; D008113:Liver Neoplasms / Q000188:drug therapy*; D008168:Lung / Q000187:drug effects / Q000502:physiology*; D008175:Lung Neoplasms / Q000188:drug therapy*; D009924:Organ Culture Techniques; D013274:Stomach Neoplasms / Q000188:drug therapy*
D015251:Epirubicin; D000077146:Irinotecan; D003520:Cyclophosphamide; D002166:Camptothecin
ADME; lab-on-a-chip; microfluidics; microtechnology