In Situ Parameter Estimation

The permeability values of CNV97100, a fluoroquinolone derivative, were obtained in different segments of rat small intestine. The compound was in solution and the pH of the perfusion fluids in each segment were the same. The permeability was lower in the terminal segment of the small intestine in accordance with the higher expression level of P-gp. In order to confirm that a saturable carrier was present, experiments at different concentrations of the quinolone were performed in the ileum and also in the whole small intestine. In both cases a non-linear correlation between permeability and concentration was found where, at the higher concentrations, the permeability values were higher thanks to saturation of the secretion transporter. 

The permeability values obtained in the different intestinal segments and at different initial concentrations are shown in Fig. 4.10. 

Data from whole small intestine, duodenum, and ileum were fitted simultaneously. This simultaneous analysis invoked the following assumptions  

Passive diffusional permeability was the same along the entire gastrointestinal tract, as the experiments were performed at the same luminal pH value. 

The maximal efflux velocity (Vm) depended on the P-gp secretion transporter expression level. A baseline value was taken to be the expression level in ileum (Vmi). The value of maximal velocity in duodenum (Vmn) and jejunum (Vmj) was computed from the baseline value and a correction factor (Ej), based on 

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