Figure 4.

Observed (red dots) in vitro Transwell data (amount, pmol) and the corresponding predicted values (green lines) using the five‐compartmental (5C) model in the absence and presence of tariquidar (P‐gp inhibitor). The model predicted the amount in the receiver compartment well, but, due to the scatter in the data, did not predict as well the amount in the donor compartment (N‐desmethyl loperamide and metoclopramide). Intrinsic in vitro clearances were estimated as follows: Passive diffusion clearances and f_u,m (unbound fraction in membrane) were estimated from (+) tariquidar data sets. After fixing these parameters to these estimates, P‐gp–mediated clearance was estimated from (−) tariquidar data sets. In all instances, parameters were estimated by simultaneously fitting the model to both the A → B and B → A data sets. Experiments at each timepoint were conducted in triplicate. AB, apical‐to‐basal; BA, basal‐to‐apical; P‐gp, P‐glycoprotein; s, seconds. [Colour figure can be viewed at wileyonlinelibrary.com]