Design and application of microfluidic systems for in vitro pharmacokinetic evaluation of drug candidates

Abstract

One of the fundamental challenges facing the development of new chemical entities within the pharmaceutical industry is the extrapolation of key in vivo parameters from in vitro cell culture assays and animal studies. Development of microscale devices and screening assays incorporating primary human cells can potentially provide better, faster and more efficient prediction of in vivo toxicity and clinical drug performance. With this goal in mind, large strides have been made in the area of microfluidics to provide in vitro surrogates that are designed to mimic the physiological architecture and dynamics. More recent advancements have been made in the development of in vitro analogues to physiologically-based pharmacokinetic (PBPK) models - a mathematical model that represents the body as interconnected compartments specific for a particular organ. In this review we highlight recent advancements in human hepatocyte microscale culture, and describe the next generation of integrated devices, whose potential allows for the high throughput assessment of drug metabolism, distribution and pharmacokinetics.

Fig. 1

Top: Diagram of the metabolism microfluidic device comprises of a liver compartment and a reservoir. The liver chamber is the sole elimination compartment of the system. Bottom: the side view of the liver chamber, where the hepatocytes are cultured. The fluid (culture medium or buffer) from and to the reservoir can flow through the liver compartment.

Fig. 2

Top: Diagram of an absorption microfluidic device comprises of an absorption compartment and a reservoir. The absorption chamber has apical and basolateral sides separated by a permeable membrane. Bottom: the side view of the absorption chamber, where Caco-2 cells are cultured on a permeable membrane. The fluid (culture medium or buffer) from and to the reservoir can flow through the absorption compartment. The dosing solution is in contact with the Caco-2 cells from the top.

Fig. 3

Top: Diagram of a bioavailability microfluidic device comprises of an absorption compartment, a metabolism compartment and a reservoir. Bottom: the side view of the absorption and the metabolism compartment. The fluid (culture medium or buffer) from the reservoir flows through the absorption compartment first, then the metabolism compartment. The drug solution first permeates through the Caco-2 monolayer, and then passes through the liver compartment to encounter the first-pass metabolism.

Fig. 4

Top: Diagram of a pharmacokinetic microfluidic device comprises of an absorption compartment, a metabolism compartment, a biodistribution compartment and a reservoir. The fluid (culture medium or buffer) from the reservoir splits in certain proportion and flows through the absorption compartment or the biodistribution compartment. The fraction flows through the absorption compartment then enter the metabolism compartment simulating the first-pass metabolism. The fraction flows through the biodistribution compartment provides tissue binding effect. Both fractions merge before entering the reservoir. Bottom: the side view of the absorption and the metabolism compartments.