Assessment of hepatic metabolism-dependent nephrotoxicity on an organs-on-a-chip microdevice

Abstract

Drug-induced nephrotoxicity is one of the most frequent adverse events in pharmacotherapy. It has resulted in numerous clinical trial failures and high drug development costs. The predictive capabilities of existing in vitro models are limited by their inability to recapitulate the complex process of drug metabolism at the multi-organ level in vivo. We present a novel integrated liver-kidney chip that allows the evaluation of drug-induced nephrotoxicity following liver metabolism in vitro. The liver-kidney chip consists of two polydimethylsiloxane layers with compartmentalized micro-channels separated by a porous membrane. Hepatic and renal cells were co-cultured in separate micro-chambers on a single chip. Ifosfamide and verapamil were used as model drugs, and their metabolites produced by hepatic metabolism were identified using mass spectrometry, respectively. The metabolites triggered significantly distinct nephrotoxic effects as assessed by cell viability, lactate dehydrogenase leakage and permeability of renal cells. This in vitro liver-kidney model facilitates the characterization of drug metabolism in the liver as well as the assessment of subsequent nephrotoxicity in a single assay. Obviously, this multi-organ platform is simple and scalable, and maybe widely applicable to the evaluation of drug metabolism and safety during the early phases of drug development.

Keywords: Drug testing; Hepatic metabolism; Microfluidics; Nephrotoxicity; Organs-on-a-chip.