Microfluidic biochip for the perifusion of precision-cut rat liver slices for metabolism and toxicology studies.
Early detection of kinetic, metabolic, and toxicity (ADME-Tox) profiles for new drug candidates is of crucial importance during drug development. This article describes a novel in vitro system for the incubation of precision-cut liver slices (PCLS) under flow conditions, based on a poly(dimethylsiloxane) (PDMS) device containing 25-microL microchambers for integration of the slices. The microdevice is coupled to a perifusion system, which enables a constant delivery of nutrients and oxygen and a continuous removal of waste products. Both a highly controlled incubation environment and high metabolite detection sensitivity could be achieved using microfluidics. Liver slices were viable for at least 24 h in the microdevice. The compound, 7-ethoxycoumarin (7-EC), was chosen to test metabolism, since its metabolism includes both phase I and phase II metabolism and when tested in the conventional well plate system, correlates well with the in vivo situation (De Kanter et al. 2004. Xenobiotica 34(3): 229-241.). The metabolic rate of 7-EC was found to be 214 +/- 5 pmol/min/mg protein in the microdevice, comparable to well plates, and was constant over time for at least 3 h. This perifusion system better mimics the in vivo situation, and has the potential to significantly contribute to drug metabolism and toxicology studies of novel chemical entities.
van Midwoud
Paul M
PM
Pharmaceutical Analysis, Department of Pharmacy, Toxicology and Targeting, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, the Netherlands.
Groothuis
Geny M M
GM
Merema
Marjolijn T
MT
Verpoorte
Elisabeth
E
D000818:Animals; D002470:Cell Survival; D003374:Coumarins / Q000737:chemistry / Q000633:toxicity*; D006863:Hydrogen-Ion Concentration; D008658:Inactivation, Metabolic; D008099:Liver / Q000378:metabolism*; D008297:Male; D044085:Microfluidics / Q000191:economics; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D046509:Tissue Culture Techniques; D014116:Toxicology / Q000295:instrumentation* / Q000379:methods
D003374:Coumarins; C017299:7-ethoxycoumarin