Analysis of Non-linear Pharmacokinetics of P-Glycoprotein Substrates in a Microfluidic Device Using a Mathematical Model that Includes an Unstirred Water Layer (UWL) Compartment.

ABSTRACT

PURPOSE: The purpose of this research is to analyze non-linear pharmacokinetics of P-glycoprotein (P-gp) substrates in a cell based assay of a microfluidic device, which might be affected by hydrodynamic barrier (unstirred water layer, UWL). RESULTS: Apparent permeability (Papp) were obtained using non-P-gp substrates (propranolol, metoprolol, and atenolol) and P-gp substrates (quinidine and talinolol) in a commercially available microfluidic device, organoplate ® of Caco-2 cell based assay. The previous UWL resistance model was well fitted to Papp of static and flow condition by assuming UWL including and negligible condition, while P-gp substrates of higher passive permeability (quinidine) was apart from the fitting curve. The concentration dependent non-linear kinetics of P-gp substrates, quinidine and talinolol, was more analyzed in detail, and apparent Vmax discrepancy between static and flow assay condition in the quinidine assay was observed, while that was not observed in talinolol, the lower permeable substrate. Based on the experimental results, a mathematical model for P-gp substrates including UWL compartment on the previous 3-compartment model was developed, and it indicated that the apparent Vmax was variable along with the ratio between passive permeability and UWL permeability. CONCLUSIONS: The mathematical model adding UWL compartment well explained non-linear pharmacokinetics of apparent permeability of P-gp substrate in the microfluidic device. The model also has a potential to be applied to P-gp substrate permeability analysis in vivo.