Evaluation of the appropriate time range for estimating the apparent permeability coefficient (P(app)) in a transcellular transport study

Abstract

In a transcellular transport study, the apparent permeability coefficient (Papp) of a compound is evaluated using the range by which the amount of compound accumulated on the receiver side is assumed to be proportional to time. However, the time profile of the concentration of the compound in receiver (C3) often shows a lag time before reaching the linear range and later changes from linear to steady state. In this study, the linear range needed to calculate Papp in the C3-time profile was evaluated by a 3-compartment model. C3 was described by an equation with two steady states (C3=A3(1-e(-αt))+B3(1-e(-βt)), α>β), and by a simple approximate line (C3=A3-A3×αt) in the time range of 3/α<t<0.3/β; the lag time, defined as the interception of the x axis, was described as 1/α. The rate constant α was affected by the membrane permeability clearance and intracellular unbound fraction, while β was affected only by the former. The linear range that was approximated in the present study was not uniformly defined within the time interval in which C3 remains at <10% of the loading concentration, which is reported as the sink condition. In conclusion, this theoretical approach showed that the appropriate time range to evaluate Papp was 3/α<t<0.3/β.

Keywords: Apparent permeability coefficient; Caco-2 cells; Intracellular distribution; Membrane permeability; Model analysis; Transcellular transport.