This permeability value has been assigned a weight factor of 150, as suggested by Pardridge and coworkers for in vitro permeability compared to in vivo permeability values measured in rats. Step III Calculation of the permeability surface area product and P gp mediated efflux clearance of the P gp substrate into mice brain and heart The P gp mediated efflux sellckchem clearance has been found to be tissue dependent. Thus, P gp expression levels in various tissues of WT mice were used in our work to account for this tissue specificity. Since the Caco 2 cells line derives from human colon carcinoma and its characteristics are similar to intestinal epithelial cells, the intestinal tissue was chosen as the reference tissue for P gp expression level.

In each of the other mice tissues, the P gp Inhibitors,Modulators,Libraries expression level has been estimated as a fraction of mice intestine P gp expression and presented in Table 3. We estimated CLP gp, t, and PSAt both expressed in Lmin Assessing drug distribution in tissues expressing Inhibitors,Modulators,Libraries P gp To investigate the ability of the developed PBPK model to assess the impact of P gp activity modulation, we used tissue concentration of 3H domperidone measured in adult male FVB WT and mdr1a1b KO mice after an IV injection at the target dose of 5 mgkg. Blood, plasma, cerebral and cardiac tissue concentrations were available at 4 and 120 min post dose, while WT liver concentra tions were available at 4, 7, 15, 30, 60 and 120 min post dose.

While the accessible data set in heart and brain tissues Inhibitors,Modulators,Libraries was limited in terms of the number of time points, it had the potential of asserting the quality of the model in those most strategic and informative regions of the lineshape, ie, near the peak concentration and at the elimination phase. We have also exploited a full data set available for WT Inhibitors,Modulators,Libraries liver to encompass the important aspect of hepatic disposition. The domperidone physicochem ical characteristics required as input parameters to the model are extracted Inhibitors,Modulators,Libraries from literature and presented in Table 4. Results Estimation of metabolic parameters Since the drug was administered intravenously, the liver was considered as the only site of clearance by metabolism. We extrapolated NCYP450 to a value of 14 nmol for a 30 g BW mouse from the log log regression calculated from published data and presented in Figure 3. The kinetic parameters of domperidone biotransformation, Km and selleck chem Vmax, were esti mated to 130 uM and 4. 6 nmolnmolP450min, respectively. Estimation of distribution parameters for WS and MTB modelst Cl The tissue to plasma partition coefficients of domper idone determined by the tissue composition based approach are listed in Table 1.