Modeling Pharmacokinetic Profiles for Assessment of Anti-Cancer Drug on a Microfluidic System

Abstract

The pharmacokinetic (PK) properties of drug, which include drug absorption and excretion, play an important role in determining the in vivo pharmaceutical activity. However, current in vitro systems that model PK profiles are often limited by the in vivo-like concentration profile of a drug. Herein, we present a perfused and multi-layered microfluidic chip system to model the PK profile of anti-cancer drug 5-FU in vitro. The chip device contains two layers of culture channels sandwiched by a porous membrane, which allows for drug exposure and diffusion between the two channels. The integration of upper intestine cells (Caco-2) and bottom targeted cells within the device enables the generation of loading and clearance portions of a PK curve under peristaltic flow. Fluorescein as a test molecule was initially used to generate a concentration-time curve, investigating the effects of parameters of flow rate, administration time, and initial concentration on dynamic drug concentration profiles. Furthermore, anti-cancer drug 5-FU was performed to assess its pharmaceutical activity on target cells (human lung adenocarcinoma cells or human pulmonary alveolar epithelial cells) using different drug administration regimens. A dynamic, in vivo-like 5-FU exposure refers to PK profile regimen, led to generate a lower drug concentration (dynamically fluctuate from 0 to 1 μg/mL affected by absorption) compared to the constant exposure. Moreover, the PK profile regimen alleviates the drug-induced cytotoxicity on target cells. These results demonstrate the feasibility of determining the PK profiles using this microfluidic system with in vivo-like drug administration regimens. This established system may provide a powerful platform for the prediction of drug safety and effectiveness in the pharmaceutical research.

Intestinal explant barrier chip: long-term intestinal absorption screening in a novel microphysiological system using tissue explants

“…S8a and b FITC or FITC-dextran conjugates are frequently used to assess the integrity of epithelial barriers in vitro. While many studies use large molecular weight FITC-dextran conjugates of ≥20 kDa, 16,18,21,44,[56][57][58][59][60] we chose to use a marker molecule with a much smaller molecular weight of 4 kDa. The smaller the molecule used for such measurements, the better it confirms maintained barrier integrity.…”

A quantitative meta-analysis comparing cell models in perfused organ on a chip with static cell cultures

“…Finally, is it desirable to connect different organs or tissue models together and is the medium routing speed and volume between tissue models important? The different OOC coculture models are challenging and is highly driven by pharmacometrics 56 , 58 , 89 , 109 , 138 rather than other types of organ-to-organ communication that does not necessary involve the liver for breakdown of compounds. The pharmacodynamics is often fast such as hours or less while endo- and paracrine signalling could be far slower and could likely be supported by slower means of transport than flow such as diffusion over short distances.…”

Intestine‐on‐a‐chip for intestinal disease study and pharmacological research

“…The pharmacokinetics of anti-cancer drugs were analyzed by using an intestine-on-a-chip or using the intestine chip coupled with other organ chips, such as liver and lung, which can emulate various physiology conditions, including the structure of internal circulation, volume ratios between organs, and blood flow ratio of the portal vein to the hepatic artery. 115,116 Haan et al integrated three organ chips including the mouth, stomach, and small intestine to model the digestive process. Digestion of nutrients like starch and casein by enzymes in each separated chamber was illustrated by the multi-organ model.…”

“…Intestine‐on‐a‐chip has been used to study the pharmacokinetics of drugs. The pharmacokinetics of anti‐cancer drugs were analyzed by using an intestine‐on‐a‐chip or using the intestine chip coupled with other organ chips, such as liver and lung, which can emulate various physiology conditions, including the structure of internal circulation, volume ratios between organs, and blood flow ratio of the portal vein to the hepatic artery 115,116 . Haan et al.…”