[Biomicrofluidics] Drug absorption related nephrotoxicity assessment on an intestine-kidney chip
Drug absorption in the intestine is tightly related to drug-induced nephrotoxicity, which is a relatively common side effect in clinical practice. It highlights a great need to develop predictive models with high accuracy in the early stage during new drug discovery and development. Herein, we presented a novel intestine-kidney chip, which recapitulated drug absorption in the intestine and its resultant drug toxicity on the kidney. This work aims to provide an integrated tool for accurate assessment of drug absorption-related nephrotoxicity in vitro. A microfluidic device with multi-interfaces was designed, which facilitated the co-culture of the intestinal and glomerular endothelial cells in compartmentalized micro-chambers. Thus, drug absorption and following nephrotoxicity could be explored in a single assay based on the formation of the intact intestine function on the chip. Specifically, we adopt digoxin (DIG) as a model drug combined with colestyramine (COL) or Verapamil (VER), which significantly influence DIG absorption in the intestine. Different degrees of nephrotoxicity under drug combinations were further observed on the chip, including cell apoptosis, cell viability, and lactate dehydrogenase leakage. These features were consistent with the variance of DIG absorption by the intestinal cells. In agreement with clinical observations, our data demonstrated that DIG-induced nephrotoxicity was enhanced combined with VER but weakened with COL. All of these findings suggest that the established microdevice might provide a useful and cost-effective platform in vitro for testing drug absorption and nephrotoxicity in preclinical trials during new drug development.
Zhongyu Li1,2,3, Wentao Su2, Yujuan Zhu1,2,3, Tingting Tao2, Dong Li4, Xiaojun Peng1, and Jianhua Qin2,3,a)lessHide Affiliations 1College of Chemistry, Dalian University of Technology, Dalian 116024, China 2Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China 3University of Chinese Academy of Sciences, Beijing 100049, China 4Dalian Municipal Women and Children's Medical Center, Dalian 116024, China a)Email: firstname.lastname@example.org. Tel.: 86-411-84379650. Fax: 86-411-84379059.
Biomicrofluidics 11, 034114 (2017); doi: http://dx.doi.org/10.1063/1.4984768